40 results on '"Petrungaro S"'
Search Results
2. A novel role of c-FLIP protein in regulation of autophagy-dependent cell death
- Author
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Tomaipitinca, L, Petrungaro, S, Filippini, A, Cecconi, F, Giampietri, C, and Ziparo, E.
- Published
- 2017
3. Therapeutic implications of autophagy modulation in prostate cancer
- Author
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Giampietri, C., Petrungaro, S., Facchiano, A., Filippini, A., and Ziparo, E.
- Published
- 2012
- Full Text
- View/download PDF
4. Gorana Ognjenovic and Jasna Jozelic: Nationalism and the Politicization of History in the Former Yugoslavia
- Author
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Petrungaro Stefano
- Subjects
History (General) and history of Europe ,Political science - Published
- 2022
- Full Text
- View/download PDF
5. Autophagy modulation increases sensitivity of prostate epithelial cancer cell lines to TNF-alpha dependent apoptosis
- Author
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Giampietri, C, Petrungaro, S, D'Alessio, Alessio, Marini, E, Filippini, A, and Ziparo, E.
- Subjects
Autophagy ,Prostate ,TNF ,Settore BIO/17 - ISTOLOGIA - Published
- 2011
6. The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria
- Author
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Marini, E S, primary, Giampietri, C, additional, Petrungaro, S, additional, Conti, S, additional, Filippini, A, additional, Scorrano, L, additional, and Ziparo, E, additional
- Published
- 2014
- Full Text
- View/download PDF
7. c-FLIP expression and function in fetal mouse gonocytes
- Author
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Giampietri, C., Petrungaro, S., Klinger, F. G., Paone, P. COLUCCIA A., Vivarelli, E., Filippini, A., DE CESARIS, Paola, DE FELICI, M., and Ziparo, E.
- Published
- 2006
8. c-Flip(L) is expressed in undifferentiated mouse male germ cells
- Author
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Giampietri, C, Petrungaro, S, Coluccia, P, Antonangeli, F, Paone, A, Padula, F, DE CESARIS, Paola, Ziparo, E, and Filippini, A.
- Published
- 2006
9. c-FLIP protects fetal gonocytes from apoptosis
- Author
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Giampietri, C, Petrungaro, S., Klinger, F., Fera, S., Riccioli, A., Vivarelli, E., Ziparo, E., Filippini, A., De Felici, M., and DE CESARIS, Paola
- Published
- 2003
10. c-Flip overexpression affects satellite cell proliferation and promotes skeletal muscle aging
- Author
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Giampietri, C, primary, Petrungaro, S, additional, Coluccia, P, additional, Antonangeli, F, additional, Giannakakis, K, additional, Faraggiana, T, additional, Filippini, A, additional, Cossu, G, additional, and Ziparo, E, additional
- Published
- 2010
- Full Text
- View/download PDF
11. The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria.
- Author
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Marini, E S, Giampietri, C, Petrungaro, S, Conti, S, Filippini, A, Scorrano, L, and Ziparo, E
- Subjects
CASPASE inhibitors ,MITOCHONDRIA ,MORPHOLOGY ,CROSSTALK ,ENDOPLASMIC reticulum - Abstract
Components of the death receptor-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIP
L ), a well-known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca2+ -release as well as ER-mitochondria tethering was decreased in c-FLIP−/− mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIPL and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIPL emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
12. FLIP is expressed in mouse testis and protects germ cells from apoptosis
- Author
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Giampietri, C, primary, Petrungaro, S, additional, Coluccia, P, additional, D'Alessio, A, additional, Starace, D, additional, Riccioli, A, additional, Padula, F, additional, Srinivasula, S M, additional, Alnemri, E, additional, Palombi, F, additional, Filippini, A, additional, Ziparo, E, additional, and De Cesaris, P, additional
- Published
- 2003
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- View/download PDF
13. c-Flip overexpression reduces cardiac hypertrophy in response to pressure overload.
- Author
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Giampietri C, Petrungaro S, Musumeci M, Coluccia P, Antonangeli F, De Cesaris P, Filippini A, Marano G, Giampietri, Claudia, Petrungaro, Simonetta, Musumeci, Marco, Coluccia, Pierpaolo, Antonangeli, Fabrizio, De Cesaris, Paola, Filippini, Antonio, Marano, Giuseppe, and Ziparo, Elio
- Published
- 2008
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14. Effect of Follicle-stimulating Hormone on Cyclic Adenosine Monophosphate Level and on Meiotic Maturation in Mouse Cumulus Cell-enclosed Oocytes Cultured in Vitro1
- Author
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Salustri, A., Petrungaro, S., De Felici, M., Conti, M., and Siracusa, G.
- Abstract
We have reported that in vitro treatment with follicle-stimulating hormone (FSH) delays by about 3 h spontaneous meiotic resumption in cumulus cell-enclosed mouse oocytes. In the present paper we show that the temporary meiotic block is accompanied by a transient increase of cAMP concentration in the oocyte. In cumulus cell-oocyte complexes stimulated with 1 μg/ml FSH, cAMP significantly increases within 1 h both in the whole complex (from a basal value of 1.9 ± 0.2 to 169 ± 13 fmol) and in the enclosed oocyte (from 0.9 ± 0.2 to 2.4 ± 0.2 fmol), then progressively decreases to basal values. Stimulation by FSH does not cause any cAMP increase in denuded oocytes. As the concentration of cAMP in the cells decreases, the percentage of oocytes escaping the meiotic block imposed by FSH increases. If the complexes are cultured in the presence of 1 μg/m1 FSH plus 1 mM isobutyl-1-methylxanthine (IBMX), cAMP concentration increases approximately 250-fold in the complex, and 10-fold in the enclosed oocyte; the level of cAMP in the oocyte drops very rapidly (50% degradation in less than 2 min) if the oocyte is then transferred to IBMX-free medium. The data are discussed in terms of the possible role of cAMP transfer from cumulus cells to the oocyte in the regulation of meiotic progression in mouse oocytes.
- Published
- 1985
- Full Text
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15. Effect of follicle-stimulating hormone on cyclic adenosine monophosphate level and on meiotic maturation in mouse cumulus cell-enclosed oocytes cultured in vitro
- Author
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Salustri, A, Petrungaro, S, DE FELICI, M, Conti, M, and Siracusa, G
- Subjects
Kinetics ,Meiosis ,Mice ,Cultured ,Settore BIO/17 ,1-Methyl-3-isobutylxanthine ,Cells ,Radioimmunoassay ,Cyclic AMP ,Oocytes ,Animals ,Follicle Stimulating Hormone ,Cells, Cultured - Published
- 1985
16. Adenosine potentiates the delaying effect of dbcAMP on meiosis resumption in denuded mouse oocytes
- Author
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PETRUNGARO, S, primary, SALUSTRI, A, additional, and SIRACUSA, G, additional
- Published
- 1986
- Full Text
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17. Adenosine potentiates forskolin‐induced delay of meiotic resumption by mouse denuded oocytes: Evidence for an oocyte surface site of adenosine action
- Author
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Salustri, A., primary, Petrungaro, S., additional, Conti, M., additional, and Siracusa, G., additional
- Published
- 1988
- Full Text
- View/download PDF
18. Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFβ Signaling in a Model of Perineural Invasion.
- Author
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de Franchis V, Petrungaro S, Pizzichini E, Camerini S, Casella M, Somma F, Mandolini E, Carpino G, Overi D, Cardinale V, Facchiano A, Filippini A, Gaudio E, Fabrizi C, and Giampietri C
- Subjects
- Humans, Bile Ducts, Intrahepatic pathology, Cell Line, Tumor, Phenotype, Proteomics, Schwann Cells pathology, Transforming Growth Factor beta genetics, Neoplasm Invasiveness, Bile Duct Neoplasms pathology, Cholangiocarcinoma pathology
- Abstract
The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial-mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFβ signaling in regulating this process.
- Published
- 2024
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19. Autophagy impairment in human bile duct carcinoma cells.
- Author
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Petrungaro S, de Franchis V, Filippini A, Facchiano A, Gaudio E, and Giampietri C
- Abstract
Bile duct epithelial cells, named cholangiocytes, may undergo a neoplastic transformation leading to cholangiocarcinoma. The role autophagy plays in cancer is still debated and few information are available in cholangiocarcinoma. We report in vitro data, at least in part validated in vivo, i ndicating that autophagy is impaired in intrahepatic cholangiocarcinoma cells, as compared to healthy cholangiocytes, evaluated through LC3II and p62 Western blot analyses. Autophagy impairment was found to be associated with low expression of TFEB protein and high expression of three proteins i.e., c-FLIP, caspase-10 and cleaved BCLAF-1, as compared to healthy cholangiocytes. We highlight biological effects of autophagy impairment in cholangiocarcinoma showing that autophagy induction, via rapamycin, as well as caspase inhibition, via Q-VD-OPh, are able to reduce proliferation marker PCNA level, colony size and protein content of cultured cholangiocarcinoma cells. The increased protein expression of p62, c-FLIP, caspase-10 observed in vitro in cholangiocarcinoma cells was paralleled by significant increase at gene expression levels in vivo ; in fact, significant increase of transcript levels of p62, c-FLIP and caspase-10 was observed in 34 biopsies from human cholangiocarcinoma patients compared to 9 biopsies from 9 healthy controls, as reported in the GEPIA2 public database. The significant increase of p62 level in cholangiocarcinoma was found as a relatively uncommon finding in solid cancers, since it was also found in only 7 cancer types out of 31 cancer types investigated, including melanoma and hepatocarcinoma. In conclusion, we present data suggesting a molecular machinery controlling autophagy in cholangiocytes and autophagy impairment in cholangiocarcinoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Petrungaro, de Franchis, Filippini, Facchiano, Gaudio and Giampietri.)
- Published
- 2023
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20. Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications.
- Author
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Sideri S, Petragnano F, Maggio R, Petrungaro S, Catizone A, Gesualdi L, De Martino V, Battafarano G, Del Fattore A, Liguoro D, De Cesaris P, Filippini A, Marampon F, and Riccioli A
- Abstract
The use of a higher dose per fraction to overcome the high radioresistance of prostate cancer cells has been unsuccessfully proposed. Herein, we present PC3 and DU-145, castration-resistant prostate cancer cell lines that survived a clinically used ultra-higher dose per fraction, namely, radioresistant PC3 and DU-145 cells (PC3RR and DU-145RR). Compared to PC3, PC3RR showed a higher level of aggressive behaviour, with enhanced clonogenic potential, DNA damage repair, migration ability and cancer stem cell features. Furthermore, compared to PC3, PC3RR more efficiently survived further radiation by increasing proliferation and down-regulating pro-apoptotic proteins. No significant changes of the above parameters were described in DU-145RR, suggesting that different prostate cancer cell lines that survive ultra-higher dose per fraction do not display the same grade of aggressive phenotype. Furthermore, both PC3RR and DU-145RR increased antioxidant enzymes and mesenchymal markers. Our data suggest that different molecular mechanisms could be potential targets for future treatments plans based on sequential strategies and synergistic effects of different modalities, possibly in a patient-tailored fashion. Moreover, PC3RR cells displayed an increase in specific markers involved in bone remodeling, indicating that radiotherapy selects a PC3 population capable of migrating to secondary metastatic sites. Finally, PC3RR cells showed a better sensitivity to Docetaxel as compared to native PC3 cells. This suggests that a subset of patients with castration-resistant metastatic disease could benefit from upfront Docetaxel treatment after the failure of radiotherapy.
- Published
- 2022
- Full Text
- View/download PDF
21. c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability.
- Author
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Tomaipitinca L, Petrungaro S, D'Acunzo P, Facchiano A, Dubey A, Rizza S, Giulitti F, Gaudio E, Filippini A, Ziparo E, Cecconi F, and Giampietri C
- Subjects
- Animals, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Fibroblasts pathology, HEK293 Cells, Humans, Mice, Molecular Docking Simulation, Nedd4 Ubiquitin Protein Ligases metabolism, Proteasome Endopeptidase Complex metabolism, Protein Binding, Protein Stability, Ubiquitination, Autophagy, Beclin-1 metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Fibroblasts metabolism
- Abstract
c-FLIP (cellular FLICE-like inhibitory protein) protein is mostly known as an apoptosis modulator. However, increasing data underline that c-FLIP plays multiple roles in cellular homoeostasis, influencing differently the same pathways depending on its expression level and isoform predominance. Few and controversial data are available regarding c-FLIP function in autophagy. Here we show that autophagic flux is less effective in c-FLIP-/- than in WT MEFs (mouse embryonic fibroblasts). Indeed, we show that the absence of c-FLIP compromises the expression levels of pivotal factors in the generation of autophagosomes. In line with the role of c-FLIP as a scaffold protein, we found that c-FLIP
L interacts with Beclin-1 (BECN1: coiled-coil, moesin-like BCL2-interacting protein), which is required for autophagosome nucleation. By a combination of bioinformatics tools and biochemistry assays, we demonstrate that c-FLIPL interaction with Beclin-1 is important to prevent Beclin-1 ubiquitination and degradation through the proteasomal pathway. Taken together, our data describe a novel molecular mechanism through which c-FLIPL positively regulates autophagy, by enhancing Beclin-1 protein stability.- Published
- 2021
- Full Text
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22. Anti-tumor Effect of Oleic Acid in Hepatocellular Carcinoma Cell Lines via Autophagy Reduction.
- Author
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Giulitti F, Petrungaro S, Mandatori S, Tomaipitinca L, de Franchis V, D'Amore A, Filippini A, Gaudio E, Ziparo E, and Giampietri C
- Abstract
Oleic acid (OA) is a component of the olive oil. Beneficial health effects of olive oil are well-known, such as protection against liver steatosis and against some cancer types. In the present study, we focused on OA effects in hepatocellular carcinoma (HCC), investigating responses to OA treatment (50-300 μM) in HCC cell lines (Hep3B and Huh7.5) and in a healthy liver-derived human cell line (THLE-2). Upon OA administration higher lipid accumulation, perilipin-2 increase, and autophagy reduction were observed in HCC cells as compared to healthy cells. OA in the presence of 10% FBS significantly reduced viability of HCC cell lines at 300 μM through Alamar Blue staining evaluation, and reduced cyclin D1 expression in a dose-dependent manner while it was ineffective on healthy hepatocytes. Furthermore, OA increased cell death by about 30%, inducing apoptosis and necrosis in HCC cells but not in healthy hepatocytes at 300 μM dosage. Moreover, OA induced senescence in Hep3B, reduced P-ERK in both HCC cell lines and significantly inhibited the antiapoptotic proteins c-Flip and Bcl-2 in HCC cells but not in healthy hepatocytes. All these results led us to conclude that different cell death processes occur in these two HCC cell lines upon OA treatment. Furthermore, 300 μM OA significantly reduced the migration and invasion of both HCC cell lines, while it has no effects on healthy cells. Finally, we investigated autophagy role in OA-dependent effects by using the autophagy inducer torin-1. Combined OA/torin-1 treatment reduced lipid accumulation and cell death as compared to single OA treatment. We therefore concluded that OA effects in HCC cells lines are, at least, in part dependent on OA-induced autophagy reduction. In conclusion, we report for the first time an autophagy dependent relevant anti-cancer effect of OA in human hepatocellular carcinoma cell lines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Giulitti, Petrungaro, Mandatori, Tomaipitinca, de Franchis, D'Amore, Filippini, Gaudio, Ziparo and Giampietri.)
- Published
- 2021
- Full Text
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23. The Role of Autophagy in Liver Epithelial Cells and Its Impact on Systemic Homeostasis.
- Author
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Tomaipitinca L, Mandatori S, Mancinelli R, Giulitti F, Petrungaro S, Moresi V, Facchiano A, Ziparo E, Gaudio E, and Giampietri C
- Subjects
- Bile Ducts cytology, Cell Death, Diet, Dyslipidemias, Endothelial Cells physiology, Energy Intake, Hepatocytes physiology, Humans, Kupffer Cells physiology, Lipid Metabolism physiology, Lipolysis, Melanoma, Muscle, Skeletal metabolism, Neoplasms, Oxidative Stress, Autophagy physiology, Epithelial Cells physiology, Homeostasis physiology, Liver cytology
- Abstract
: Autophagy plays a role in several physiological and pathological processes as it controls the turnover rate of cellular components and influences cellular homeostasis. The liver plays a central role in controlling organisms' metabolism, regulating glucose storage, plasma proteins and bile synthesis and the removal of toxic substances. Liver functions are particularly sensitive to autophagy modulation. In this review we summarize studies investigating how autophagy influences the hepatic metabolism, focusing on fat accumulation and lipids turnover. We also describe how autophagy affects bile production and the scavenger function within the complex homeostasis of the liver. We underline the role of hepatic autophagy in counteracting the metabolic syndrome and the associated cardiovascular risk. Finally, we highlight recent reports demonstrating how the autophagy occurring within the liver may affect skeletal muscle homeostasis as well as different extrahepatic solid tumors, such as melanoma., Competing Interests: All the Authors declare no conflict of interest.
- Published
- 2019
- Full Text
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24. Lipid Storage and Autophagy in Melanoma Cancer Cells.
- Author
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Giampietri C, Petrungaro S, Cordella M, Tabolacci C, Tomaipitinca L, Facchiano A, Eramo A, Filippini A, Facchiano F, and Ziparo E
- Subjects
- AMP-Activated Protein Kinases metabolism, Cell Differentiation, Humans, Melanoma pathology, Neoplastic Stem Cells pathology, PPAR gamma metabolism, Phosphorylation, Sterol Regulatory Element Binding Protein 1 metabolism, TOR Serine-Threonine Kinases metabolism, Tumor Cells, Cultured, Autophagy, Lipid Metabolism, Melanoma metabolism, Neoplastic Stem Cells metabolism
- Abstract
Cancer stem cells (CSC) represent a key cellular subpopulation controlling biological features such as cancer progression in all cancer types. By using melanospheres established from human melanoma patients, we compared less differentiated melanosphere-derived CSC to differentiating melanosphere-derived cells. Increased lipid uptake was found in melanosphere-derived CSC vs. differentiating melanosphere-derived cells, paralleled by strong expression of lipogenic factors Sterol Regulatory Element-Binding Protein-1 (SREBP-1) and Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). An inverse relation between lipid-storing phenotype and autophagy was also found, since microtubule-associated protein 1A/1B-Light Chain 3 (LC3) lipidation is reduced in melanosphere-derived CSC. To investigate upstream autophagy regulators, Phospho-AMP activated Protein Kinase (P-AMPK) and Phospho-mammalian Target of Rapamycin (P-mTOR) were analyzed; lower P-AMPK and higher P-mTOR expression in melanosphere-derived CSC were found, thus explaining, at least in part, their lower autophagic activity. In addition, co-localization of LC3-stained autophagosome spots and perilipin-stained lipid droplets was demonstrated mainly in differentiating melanosphere-derived cells, further supporting the role of autophagy in lipid droplets clearance. The present manuscript demonstrates an inverse relationship between lipid-storing phenotype and melanoma stem cells differentiation, providing novel indications involving autophagy in melanoma stem cells biology., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
25. Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases.
- Author
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Mancinelli R, Carpino G, Petrungaro S, Mammola CL, Tomaipitinca L, Filippini A, Facchiano A, Ziparo E, and Giampietri C
- Subjects
- Animals, Apoptosis, Glycogen Synthase Kinase 3 genetics, Glycogen Synthase Kinase 3 beta genetics, Humans, Liver Diseases genetics, Liver Diseases pathology, Neoplasm Proteins genetics, Neoplasms genetics, Neoplasms pathology, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Oxidative Stress, Autophagy, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta metabolism, Liver Diseases enzymology, Neoplasm Proteins metabolism, Neoplasms enzymology, Neurodegenerative Diseases enzymology
- Abstract
GSK-3 is a ubiquitously expressed serine/threonine kinase existing as GSK-3 α and GSK-3 β isoforms, both active under basal conditions and inactivated upon phosphorylation by different upstream kinases. Initially discovered as a regulator of glycogen synthesis, GSK-3 is also involved in several signaling pathways controlling many different key functions. Here, we discuss recent advances regarding (i) GSK-3 structure, function, regulation, and involvement in several cancers, including hepatocarcinoma, cholangiocarcinoma, breast cancer, prostate cancer, leukemia, and melanoma (active GSK-3 has been shown to induce apoptosis in some cases or inhibit apoptosis in other cases and to induce cancer progression or inhibit tumor cell proliferation, suggesting that different GSK-3 modulators may address different specific targets); (ii) GSK-3 involvement in autophagy modulation, reviewing signaling pathways involved in neurodegenerative and liver diseases; (iii) GSK-3 role in oxidative stress and autophagic cell death, focusing on liver injury; (iv) GSK-3 as a possible therapeutic target of natural substances and synthetic inhibitors in many diseases; and (v) GSK-3 role as modulator of mammalian aging, related to metabolic alterations characterizing senescent cells and age-related diseases. Studies summarized here underline the GSK-3 multifaceted role and indicate such kinase as a molecular target in different pathologies, including diseases associated with autophagy dysregulation.
- Published
- 2017
- Full Text
- View/download PDF
26. A novel role of c-FLIP protein in regulation of ER stress response.
- Author
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Conti S, Petrungaro S, Marini ES, Masciarelli S, Tomaipitinca L, Filippini A, Giampietri C, and Ziparo E
- Subjects
- Animals, Apoptosis, Autophagy, CASP8 and FADD-Like Apoptosis Regulating Protein deficiency, Embryo, Mammalian cytology, Enzyme Activation, Fibroblasts metabolism, Membrane Proteins metabolism, Mice, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, eIF-2 Kinase metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Endoplasmic Reticulum Stress
- Abstract
Cellular-Flice-like inhibitory protein (c-FLIP) is an apoptosis modulator known to inhibit the extrinsic apoptotic pathway thus blocking Caspase-8 processing in the Death Inducing Signalling Complex (DISC). We previously demonstrated that c-FLIP localizes at the endoplasmic reticulum (ER) and that c-FLIP-deficient mouse embryonic fibroblasts (MEFs) display an enlarged ER morphology. In the present study, we have addressed the consequences of c-FLIP ablation in the ER stress response by investigating the effects of pharmacologically-induced ER stress in Wild Type (WT) and c-FLIP-/- MEFs. Surprisingly, c-FLIP-/- MEFs were found to be strikingly more resistant than WT MEFs to ER stress-mediated apoptosis. Analysis of Unfolded Protein Response (UPR) pathways revealed that Pancreatic ER Kinase (PERK) and Inositol-Requiring Enzyme 1 (IRE1) branch signalling is compromised in c-FLIP-/- cells when compared with WT cells. We found that c-FLIP modulates the PERK pathway by interfering with the activity of the serine threonine kinase AKT. Indeed, c-FLIP-/- MEFs display higher levels of active AKT than WT MEFs upon ER stress, while treatment with a specific AKT inhibitor of c-FLIP-/- MEFs subjected to ER stress restores the PERK but not the IRE1 pathway. Importantly, the AKT inhibitor or dominant negative AKT transfection sensitizes c-FLIP-/- cells to ER stress-induced cell death while the expression of a constitutively active AKT reduces WT cells sensitivity to ER stress-induced death. Thus, our results demonstrate that c-FLIP modulation of AKT activity is crucial in controlling PERK signalling and sensitivity to ER stress, and highlight c-FLIP as a novel molecular player in PERK and IRE1-mediated ER stress response., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
27. c-Flip KO fibroblasts display lipid accumulation associated with endoplasmic reticulum stress.
- Author
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Giampietri C, Petrungaro S, Conti S, Facchiano A, Filippini A, and Ziparo E
- Subjects
- Animals, Cells, Cultured, Culture Media, Serum-Free, DNA-Binding Proteins metabolism, Embryo, Mammalian, Gene Knockdown Techniques, Lipogenesis genetics, Mice, PPAR gamma metabolism, Regulatory Factor X Transcription Factors, Transcription Factors metabolism, X-Box Binding Protein 1, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Endoplasmic Reticulum Stress genetics, Fibroblasts metabolism, Lipid Metabolism genetics
- Abstract
c-Flip proteins are well-known apoptosis modulators. They generally contribute to tissue homeostasis maintenance by inhibiting death-receptor-mediated cell death. In the present manuscript, we show that c-Flip knock-out (KO) mouse embryonic fibroblasts (MEFs) kept in culture under starvation conditions gradually modify their phenotype and accumulate vacuoles, becoming progressively larger according to the duration of starvation. Large vacuoles are present in KO MEFs though not in WT MEFs, and are Oil Red-O positive, which indicates that they represent lipid droplets. Western blot experiments reveal that, unlike WT MEFs, KO MEFs express high levels of the lipogenic transcription factor PPAR-γ. Lipid droplet accumulation was found to be associated with endoplasmic reticulum (ER) stress activation and autophagic modulation valuated by means of BIP increase, LC3 lipidation and AMP-activated protein kinase (AMPK) phosphorylation, and p62 accumulation. Interestingly, XBP-1, an ER stress-induced lipogenic transcription factor, was found to preferentially localize in the nucleus rather than in the cytoplasm of KO MEFs. These data demonstrate that, upon starvation, c-Flip affects lipid accumulation, ER stress and autophagy, thereby pointing to an important role of c-Flip in the adaptive response and ER stress response programs under both normal and pathological conditions., (Copyright © 2015. Published by Elsevier B.V.)
- Published
- 2015
- Full Text
- View/download PDF
28. The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria.
- Author
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Marini ES, Giampietri C, Petrungaro S, Conti S, Filippini A, Scorrano L, and Ziparo E
- Subjects
- Animals, Endoplasmic Reticulum ultrastructure, Mice, Myelin Proteins, Nogo Proteins, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Caspase 8 metabolism, Endoplasmic Reticulum metabolism, Mitochondria metabolism, Signal Transduction
- Abstract
Components of the death receptor-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIP(L)), a well-known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca(2+)-release as well as ER-mitochondria tethering was decreased in c-FLIP(-/-) mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIP(L) and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIP(L) emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4.
- Published
- 2015
- Full Text
- View/download PDF
29. Cancer Microenvironment and Endoplasmic Reticulum Stress Response.
- Author
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Giampietri C, Petrungaro S, Conti S, Facchiano A, Filippini A, and Ziparo E
- Subjects
- Animals, Humans, Male, Melanoma metabolism, Prostatic Neoplasms metabolism, Unfolded Protein Response physiology, Endoplasmic Reticulum Stress physiology, Tumor Microenvironment physiology
- Abstract
Different stressful conditions such as hypoxia, nutrient deprivation, pH changes, or reduced vascularization, potentially able to act as growth-limiting factors for tumor cells, activate the unfolded protein response (UPR). UPR is therefore involved in tumor growth and adaptation to severe environments and is generally cytoprotective in cancer. The present review describes the molecular mechanisms underlying UPR and able to promote survival and proliferation in cancer. The critical role of UPR activation in tumor growth promotion is discussed in detail for a few paradigmatic tumors such as prostate cancer and melanoma.
- Published
- 2015
- Full Text
- View/download PDF
30. Necroptosis: molecular signalling and translational implications.
- Author
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Giampietri C, Starace D, Petrungaro S, Filippini A, and Ziparo E
- Abstract
Necroptosis is a form of programmed necrosis whose molecular players are partially shared with apoptotic cell death. Here we summarize what is known about molecular signalling of necroptosis, particularly focusing on fine tuning of FLIP and IAP proteins in the apoptosis/necroptosis balance. We also emphasize necroptosis involvement in physiological and pathological conditions, particularly in the regulation of immune homeostasis.
- Published
- 2014
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31. Autophagy in prostate cancer and androgen suppression therapy.
- Author
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Ziparo E, Petrungaro S, Marini ES, Starace D, Conti S, Facchiano A, Filippini A, and Giampietri C
- Subjects
- Animals, Disease Progression, Humans, Immunity drug effects, Male, Models, Biological, Prostatic Neoplasms immunology, Androgens pharmacology, Androgens therapeutic use, Autophagy drug effects, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology
- Abstract
The role of autophagy is known to be highly complex and context-dependent, leading to both cancer suppression and progression in several tumors including melanoma, breast and prostate cancer. In the present review, recent advances in an understanding of the involvement of autophagy in prostate cancer treatment are described. The regulatory effects of androgens on prostate cancer cell autophagy are particularly discussed in order to highlight the effects of autophagy modulation during androgen deprivation. A critical evaluation of the studies examined in the present review suggests the attractive possibility of autophagy inhibition combined with hormonal therapy as a promising approach for prostate cancer treatment.
- Published
- 2013
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32. Sex-related differences in death control of somatic cells.
- Author
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Giampietri C, Petrungaro S, Filippini A, and Ziparo E
- Subjects
- Animals, Cells, Cultured, Female, Humans, Male, Apoptosis, Sex Characteristics
- Published
- 2013
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- View/download PDF
33. Autophagy modulators sensitize prostate epithelial cancer cell lines to TNF-alpha-dependent apoptosis.
- Author
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Giampietri C, Petrungaro S, Padula F, D'Alessio A, Marini ES, Facchiano A, Filippini A, and Ziparo E
- Subjects
- Adenine analogs & derivatives, Blotting, Western, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Cell Line, Tumor, Drug Screening Assays, Antitumor, Enzyme Activation drug effects, Epithelial Cells drug effects, Epithelial Cells metabolism, Forkhead Box Protein O3, Forkhead Transcription Factors metabolism, Humans, Male, Microtubule-Associated Proteins metabolism, Promoter Regions, Genetic genetics, Prostatic Neoplasms enzymology, Proteasome Endopeptidase Complex metabolism, Proteasome Inhibitors pharmacology, Proteolysis drug effects, Proto-Oncogene Proteins c-akt metabolism, Reactive Oxygen Species metabolism, Sirolimus pharmacology, Transcription, Genetic drug effects, p38 Mitogen-Activated Protein Kinases metabolism, Apoptosis drug effects, Autophagy drug effects, Epithelial Cells pathology, Prostatic Neoplasms pathology, Tumor Necrosis Factor-alpha pharmacology
- Abstract
TNF-alpha levels in prostate cancer correlate with the extent of disease and are significantly elevated in the metastatic stage. TNF receptor superfamily controls two distinct signalling cascades, leading to opposite effects, i.e. apoptosis and survival; in prostate cancer TNF-alpha-mediated signalling induces cell survival and resistance to therapy. The apoptosis of prostate epithelial cancer cells LNCaP and PC3 was investigated upon treatment with the autophagy inhibitor 3-methyladenine and the autophagy inducer rapamycin, in combination with TNF-alpha. Cells were exposed to these molecules for 18, 24 and 48 h. Autophagy was assessed via LC3 Western blot analysis; propidium iodide and TUNEL stainings followed by flow cytometry or caspase-8 and caspase-3 activation assays were performed to evaluate apoptosis. TNF-alpha-induced apoptosis was potentiated by 3-methyladenine in the androgen-responsive LNCaP cells, whereas no effect was observed in the androgen-insensitive PC3 cells. Interestingly such pro-apoptosis effect in LNCaP cells was associated with reduced c-Flip levels through proteasomal degradation via increased reactive oxygen species production and p38 activation; such c-Flip reduction was reversed in the presence of either the proteasome inhibitor MG132 or the reactive oxygen species scavenger N-acetyl-cysteine. Conversely in PC3 but not in LNCaP cells, rapamycin stimulated TNF-alpha-dependent apoptosis; such effect was associated with reduced c-Flip promoter activity and FoxO3a activation. We conclude that TNF-alpha-induced apoptosis may be potentiated, in prostate cancer epithelial cells, through autophagy modulators. Increased sensitivity to TNF-alpha-dependent apoptosis correlates with reduced c-Flip levels which are consequent to a post-transcriptional and a transcriptional mechanism in LNCaP and PC3 cells respectively.
- Published
- 2012
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34. Testis atrophy and reduced sperm motility in transgenic mice overexpressing c-FLIP(L).
- Author
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Antonangeli F, Petrungaro S, Coluccia P, Filippini A, Ziparo E, and Giampietri C
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Atrophy, Blotting, Western, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Caspase 8 metabolism, Immunohistochemistry, In Situ Nick-End Labeling, Male, Mice, Mice, Transgenic, Promoter Regions, Genetic, Proteins genetics, Spermatogenesis, Spermatozoa pathology, Testis pathology, Up-Regulation, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Sperm Motility, Spermatozoa metabolism, Testis metabolism
- Abstract
Objective: To study the effect of c-FLIP overexpression in testicular germ cells., Design: A novel transgenic mouse model overexpressing the apoptotic modulator c-FLIP in the testis was generated., Setting: Animal facility and university research laboratory., Animal(s): Transgenic mice overexpressing the long isoform of c-FLIP (c-FLIP(L)) under the transcriptional control of a 400 bp long regulatory region of the Stra8 promoter., Intervention(s): Spermatozoa motility and testis histological, immunohistochemical, and Western blot analyses were carried out in transgenic and control derived specimens., Main Outcome Measure(s): Testis morphology, sperm motility, and germ cell apoptosis were assayed., Results: Stra8 promoter was found to activate the ectopic overexpression of c-FLIP(L) in round and elongated spermatids. As a consequence of such overexpression, a dramatic loss of germ cells was observed, resulting in testicular atrophy associated with reduced sperm motility., Conclusion(s): The data show that c-FLIP(L) forced expression in haploid male germ cells has detrimental effects on spermatogenesis and sperm quality and reveal a possible mechanism underlying the onset of testicular atrophy., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
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35. Expression profile of a 400-bp Stra8 promoter region during spermatogenesis.
- Author
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Antonangeli F, Giampietri C, Petrungaro S, Filippini A, and Ziparo E
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Animals, Newborn, Artificial Gene Fusion, Flow Cytometry, Genes, Reporter, Green Fluorescent Proteins biosynthesis, Green Fluorescent Proteins genetics, Male, Mice, Mice, Transgenic, Microscopy, Confocal, Gene Expression Regulation, Developmental, Promoter Regions, Genetic, Proteins metabolism, Spermatogenesis physiology
- Abstract
Although numerous markers have been helpful in isolating and enriching spermatogonial stem cells (SSCs), such as Thy-1 and GFR alpha-1, no specific marker for this cell type has been identified so far. A 400-bp regulatory region of the stimulated by retinoic acid gene 8 (Stra8) promoter was reported to direct gene expression into SSCs and we have recently generated a new transgenic mouse model harboring the enhanced green fluorescent protein (EGFP) downstream of this Stra8 promoter. In this study, a detailed analysis of the EGFP expression pattern in the testis was carried out, showing that the transgene was expressed in meiotic and postmeiotic germ cells and not in undifferentiated germ cells. These findings were supported by confocal microscopy and flow cytometric analyses, and do not agree with the previous report concerning the 400-bp Stra8 promoter activity., ((c) 2009 Wiley-Liss, Inc.)
- Published
- 2009
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36. c-Flip(L) is expressed in undifferentiated mouse male germ cells.
- Author
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Giampietri C, Petrungaro S, Coluccia P, Antonangeli F, Paone A, Padula F, De Cesaris P, Ziparo E, and Filippini A
- Subjects
- Animals, Caspases, Cell Differentiation, Cell Survival, Immunologic Techniques, Male, Mice, Mice, Inbred Strains, Seminiferous Tubules cytology, Testis cytology, fas Receptor, CASP8 and FADD-Like Apoptosis Regulating Protein analysis, CASP8 and FADD-Like Apoptosis Regulating Protein physiology, Germ Cells chemistry, Spermatogonia chemistry
- Abstract
Apoptosis represents a fundamental process during fetal/post-natal testis development. Therefore pro- and anti-apoptotic proteins are essential to regulate testis physiology. c-Flip(L) is a known inhibitor of caspase 8/10 activity; in this study its perinatal expression in mouse male germ cells was investigated. In testis sections and seminiferous tubule whole mount c-Flip(L) was found to be expressed in undifferentiated spermatogonia and to co-localize with germ stem cells markers. In vivo investigations in the vitamin-A deficient mouse, lacking differentiated germ cells, confirmed c-Flip(L) expression in undifferentiated spermatogonia. Further analyses showed Fas expression but no significant caspase 8/10 activity when c-Flip(L) was highly expressed. Altogether these data suggest that c-Flip may control the survival rate of undifferentiated spermatogonia.
- Published
- 2006
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37. c-Flip expression and function in fetal mouse gonocytes.
- Author
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Giampietri C, Petrungaro S, Klinger FG, Coluccia P, Paone A, Vivarelli E, Filippini A, De Cesaris P, De Felici M, and Ziparo E
- Subjects
- Animals, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 10, Caspases metabolism, Male, Mice, Receptors, Tumor Necrosis Factor metabolism, Signal Transduction, Testis metabolism, fas Receptor, Fetus cytology, Gene Expression Regulation, Developmental, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Testis cytology, Testis embryology
- Abstract
Apoptosis is a key mechanism in spermatogenesis, and in testis, most gonocytes degenerate at fetal and postnatal ages to select a cell subset committed to become germ stem cells. The aim of the present study is to investigate mechanisms controlling the massive apoptosis of fetal gonocytes. We evaluated the expression and function of c-Flip, an apoptosis inhibitor known to interfere with the proapoptotic Fas-signaling pathway in a variety of cell types, but never investigated in fetal testis. Expression of c-Flip long isoform (c-FlipL) within fetal testis was localized in gonocytes at 16.5 and 18.5 days post coitum (dpc), both at the mRNA and protein level, while it was weakly expressed or undetectable at earlier stages. Moreover, Fas protein was found in fetal testes at 13.5, 16.5, and 18.5 dpc. Testes at 18.5 dpc, expressing high levels of c-FlipL, were resistant to Fas-induced apoptosis while they became highly sensitive when c-FlipL was inhibited by antisense c-Flip oligos. In addition, there was an inverse relation between gonocyte spontaneous apoptosis sensitivity and c-FlipL levels. Furthermore, caspase-10 activity was inversely related with c-FlipL expression, suggesting that caspase-10 might be a target of c-FlipL. These data represent the first evidence demonstrating c-Flip expression in fetal testes and its role in protecting gonocytes from Fas-dependent apoptosis.
- Published
- 2006
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38. Germ cell apoptosis control during spermatogenesis.
- Author
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Giampietri C, Petrungaro S, Coluccia P, D'Alessio A, Starace D, Riccioli A, Padula F, Palombi F, Ziparo E, Filippini A, and De Cesaris P
- Subjects
- Aging, Animals, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspases metabolism, Cell Differentiation, Flow Cytometry, Immunohistochemistry, Intracellular Signaling Peptides and Proteins analysis, Intracellular Signaling Peptides and Proteins physiology, Male, Mice, Organ Culture Techniques, Protein Isoforms physiology, Sexual Maturation, Spermatocytes chemistry, Spermatocytes cytology, Spermatocytes enzymology, Spermatogonia chemistry, Spermatogonia cytology, Spermatogonia enzymology, Spermatozoa physiology, Testis chemistry, Testis cytology, Apoptosis, Spermatogenesis, Spermatozoa cytology
- Abstract
The aim of the present study was to investigate the expression and role of c-Flip long isoform (c-FlipL), a known anti-apoptotic protein. No data are currently available on c-FlipL in male gonad before puberty; therefore, this study was carried out in prepuberal mouse testis. We investigated pachytene spermatocytes and spermatogonia by immunostaining of testis sections and found a strong and specific expression of c-FlipL in pachytene spermatocytes, while spermatogonia expressed very low levels of c-FlipL. This finding inversely correlated with the caspases activity, which was higher in spermatogonia as compared to pachytene spermatocytes. Other experiments carried out in an organ-culture model revealed that Fas-induced apoptosis was higher in spermatogonia as compared to pachytene spermatocytes. These data suggest that c-FlipL may play a role as an anti-apoptotic molecule in the prepuberal mouse testis and open new perspectives in the comprehension of the mechanisms controlling germ cells apoptosis.
- Published
- 2005
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- View/download PDF
39. Characterization of signaling pathways leading to Fas expression induced by TNF-alpha: pivotal role of NF-kappaB.
- Author
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Starace D, Riccioli A, D'Alessio A, Giampietri C, Petrungaro S, Galli R, Filippini A, Ziparo E, and De Cesaris P
- Subjects
- Acetylcysteine analogs & derivatives, Acetylcysteine pharmacology, Animals, Apoptosis, Cells, Cultured, Cysteine Proteinase Inhibitors pharmacology, Enzyme Inhibitors pharmacology, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, I-kappa B Proteins metabolism, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Luciferases genetics, MAP Kinase Kinase 4, Male, Mice, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinases physiology, NF-KappaB Inhibitor alpha, NF-kappa B antagonists & inhibitors, NF-kappa B genetics, Recombinant Fusion Proteins, Sertoli Cells metabolism, Transfection, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, Gene Expression Regulation drug effects, NF-kappa B physiology, Signal Transduction, Tumor Necrosis Factor-alpha pharmacology, fas Receptor genetics
- Abstract
TNF-alpha is known to induce a strong up-regulation of Fas expression in mouse Sertoli cell cultures, leading to their apoptosis triggered by effector FasL-bearing cells. These data suggest that increased Fas expression on the cell surface might be a key event in the pathogenesis of autoimmune orchitis, by inducing a leakage of the blood-tubular barrier as a consequence of Sertoli cell apoptosis. In the present paper, we have investigated the signal transduction mechanisms involved in the regulation of Fas expression induced by TNF-alpha in mouse Sertoli cells. We studied the role of the transcription factor NF-kappaB and of MAPKs in regulating Fas expression. By using Sertoli cells transfected with a NF-kappaB Luc reporter gene, we proved that TNF-alpha activates the IkappaB/NF-kappaB system. Moreover, the use of the proteasome inhibitor lactacystin led us to demonstrate that NF-kappaB is required for TNF-alpha mediated Fas expression. By using specific inhibitors for each MAPK, we confirmed the pivotal role of the IkappaB/NF-kappaB system by demonstrating that ERKs, p38, and JNK are not involved in Fas up-regulation by TNF-alpha. The comprehension of these pathways could be relevant to the knowledge of the pathogenesis of autoimmune disorders in immune privileged districts of the body.
- Published
- 2005
- Full Text
- View/download PDF
40. Granulosa cells stimulate in vitro the expansion of isolated mouse cumuli oophori: involvement of prostaglandin E2.
- Author
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Salustri A, Petrungaro S, and Siracusa G
- Subjects
- Animals, Female, Gonadotropins, Equine pharmacology, Granulosa Cells physiology, In Vitro Techniques, Mice, Mice, Inbred Strains physiology, Ovarian Follicle physiology, Granulosa Cells drug effects, Ovarian Follicle drug effects, Prostaglandins E pharmacology
- Abstract
Granulosa cells (2 X 10(6) per ml) obtained from pregnant mare's serum gonadotropin (PMSG)-primed mice induce within 24 h the expansion in vitro of cocultured mouse cumuli oophori. Experiments with conditioned media showed that the expansion-promoting action of granulosa cells is due to diffusible factor(s) released into the culture medium. Studies with prostaglandin synthetase inhibitors and direct measurements of prostaglandin E2 (PGE2) released by granulosa cells in the culture medium have also been performed. The results strongly suggest that the cumulus oophorus expansion-promoting action of granulosa cells is mediated by PGE2, and support the hypothesis (Downs and Longo, 1983) that granulosa cells might play a similar role in the mechanism of cumulus expansion in vivo. The suggestion is advanced that coculture with granulosa cells might be of help to allow physiologic expansion in culture of immature cumuli obtained from preovulatory follicles in in vitro fertilization programs.
- Published
- 1985
- Full Text
- View/download PDF
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