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Skeletal muscle atrophy results from the net loss of muscular proteins and organelles and is caused by pathologic conditions such as nerve injury, immobilization, cancer, and other metabolic diseases. Recently, ubiquitination-mediated degradation of skeletal-muscle-specific transcription factors was shown to be involved in muscle atrophy, although the mechanisms have yet to be defined. Here we report that ret finger protein (RFP), also known as TRIM27, works as an E3 ligase in Pax7-induced degradation of MyoD. Muscle injury induced by sciatic nerve transection up-regulated RFP and RFP physically interacted with both Pax7 and MyoD. RFP and Pax7 synergistically reduced the protein amounts of MyoD but not the mRNA. RFP-induced reduction of MyoD protein was blocked by proteasome inhibitors. The Pax7-induced reduction MyoD was attenuated by RFP siRNA and by MG132, a proteasome inhibitor. RFPΔR, an RFP construct that lacks the RING domain, failed to reduce MyoD amounts. RFP ubiquitinated MyoD, but RFPΔR failed to do so. Forced expression of RFP, but not RFPΔR, enhanced Pax7-induced ubiquitination of MyoD, whereas RFP siRNA blocked the ubiquitination. Sciatic nerve injury-induced muscle atrophy as well the reduction in MyoD was attenuated in RFP knockout mice. Taken together, our results show that RFP works as a novel E3 ligase in the Pax7-mediated degradation of MyoD in response to skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Objective: Endometrial cancer is a common malignancy of the gynecological system and has been classified into two major groups, Types I and II. Type I tumors are estrogen-related, low-grade endometrioid tumors, whereas type II tumors are aggressive, high-grade non-endometrioid tumors. Ret finger protein is a nuclear transcription factor with a tripartite motif that is highly expressed in different tumor cells.Material and Method: To analyze the expression of ret finger protein in endometrial tissues and cancer, 18 cases of secretory and proliferative endometrium, endometrial polyp, endometrial hyperplasia and endometrial intraepithelial neoplasia and 21 cases of types I and II endometrial carcinoma were evaluated immunohistochemically. Results: Although rare cases of secretory endometrium showed a weak focal nuclear positivity, remaining proliferative endometrium, endometrial hyperplasia and type I endometrioid cancer cases were negative. In contrast, all cases of serous cancers showed strong nuclear positivity. After these strong positive results for serous endometrial cancer, 12 more cases of ovarian and endometrial serous carcinoma cases were added to the study. All of the additional cases were also strongly positive for ret finger protein. Conclusion: We suggest that ret finger protein might play a role in the carcinogenesis of the serous tumors of gynecological system and can be used to differentiate serous carcinomas from other epithelial tumors. [ABSTRACT FROM AUTHOR]

The RET finger protein (RFP) is a transcription factor belonging to the TRIM (tripartite motif) superfamily of proteins. RFP is expressed in a variety of human and rodent tumor cell lines and in several kinds of human cancer. Expression of RFP is associated with prognosis of colon and endometrial cancers. In the present study, we evaluated the expression of RFP in lung cancer and assessed its clinical significance. Tissue microarrays were constructed from 108 cases of lung cancer, and the sections were analyzed for RFP expression by immunohistochemistry. RFP expression was detected in the nucleus in 66.7% of lung cancer tissues examined. RFP expression was statistically significantly associated with thyroid transcription factor 1 (TTF-1) expression ( P= 0.028). However, no significant association was observed between RFP expression and other clinicopathological or genetic factors, including epidermal growth factor receptor (EGFR) mutations. Interestingly, we found that RFP expression correlated with poor prognosis in patients with EGFR mutations ( P= 0.032). Our results suggest that RFP has a role in mutated EGFR signaling and that RFP status may be a prognostic factor for lung cancer with EGFR mutations. [ABSTRACT FROM AUTHOR]

Abstract: The Scaffold attachment factor B1 (SAFB1) is an estrogen receptor (ESR1) repressor that has been proposed to inhibit breast tumorigenesis. To obtain insight into the functions of SAFB1 we utilized a yeast two-hybrid screen and identified the Ret finger protein (RFP) as interacting with the SAFB1 C-terminus. RFP is a member of the trimotif (TRIM) family of proteins, which we found widely expressed in a series of breast cancer cell lines. We confirmed the interaction between SAFB1 and RFP through in vitro (GST-pull-down) and in vivo (coimmunoprecipitations) assays. We hypothesized that SAFB1 functions as a scaffolding protein to recruit proteins such as RFP into proximity with ESR1. Consequently, we asked whether RFP would modulate ESR1 activity and we discovered that RFP was important for the ESR1-dependent expression of cyclin D1 (CCND1) and the progesterone receptor (PR), but not IRS1 or MYC. Although RFP did not interact with ESR1 directly, it does coimmunoprecipitate with ESR1, demonstrating that RFP is found within the same protein complex. Chromatin immunoprecipitation assays (ChIP) located RFP to the TFF1 promoter, a known ESR1-regulated gene. Taken together, our study provides further evidence that coactivation and corepression are integrally linked processes and that RFP is a component of an ESR1 regulatory complex. [Copyright &y& Elsevier]

Abstract: Ret finger protein (RFP) is a nuclear protein that is highly expressed in testis and in various tumor cell lines. RFP functions as a transcriptional repressor and associates with Enhancer of Polycomb 1 (EPC1), a member of the Polycomb group proteins, and Mi-2β, a main component of the nucleosome remodeling and deacetylase (NuRD) complex. We show that RFP binds with PIAS (protein inhibitor of activated STAT) proteins, PIAS1, PIAS3, PIASxα and PIASy at their carboxyl-terminal region and is covalently modified by SUMO-1 (sumoylation). PIAS proteins enhance the sumoylation of RFP in a dose-dependent manner and induce the translocation of RFP into nuclear bodies reminiscent of the PML bodies. In addition, co-expression of PIAS proteins or SUMO-1 strengthened the transcriptional repressive activity of RFP. Finally, our immunohistochemical results show that RFP, SUMO-1 and PIASy localize in a characteristic nuclear structure juxtaposed with the inner nuclear membrane (XY body) of primary spermatocytes in mouse testis. These results demonstrate that the intracellular location and the transcriptional activity of RFP are modified by PIAS proteins which possess SUMO E3 ligase activities and suggest that they may play a co-operative role in spermatogenesis. [Copyright &y& Elsevier]

The RET finger protein (RFP), which belongs to the B box zinc finger protein family, has a tripartite motif consisting of a Ring finger, a B box finger and a coiled-coil domain. The RET finger protein becomes oncogenic when its tripartite motif is fused with the tyrosine kinase domain of the RET protein. This study examined the RFP expression in normal and tumor tissues by immunohistochemistry. RFP was detected in the nuclei of various cells, including peripheral and central neurones, hepatocytes, adrenal chromaffin cells and male germ cells. Among them, RFP was expressed at high levels in male germ cells such as primary spermatocytes and round spermatids, and formed a perinuclear cap structure in primary spermatocytes. On the other hand, high levels of cytoplasmic expression of RFP were observed in some plasma cells as well as solitary plasmacytoma and multiple myeloma. These results suggested that different nuclear/cytoplasmic distributions of RFP might play a role in the regulation of growth or differentiation of different cell types. [ABSTRACT FROM AUTHOR]

Summary RET finger protein (RFP) forms a complex with histone deacetylase 1, resulting in aberrant deacetylation of H3K27ac and dysregulation of cis -regulatory elements. We evaluated the modulatory effects of RFP knockdown on cis -regulatory elements, gene expression, and chemosensitivity to temozolomide both in glioblastoma cells and in an intracranial glioblastoma model. The combination of RFP knockdown and temozolomide treatment markedly suppressed the glioblastoma cell growth due to oxidative stress and aberrant cell cycle and increased survival time in mice with glioblastoma. ChIP-seq and RNA-seq revealed that RFP knockdown increased or decreased activity of numerous cis- regulatory elements that lie adjacent to genes that control functions such as apoptosis, mitosis, DNA replication, and cell cycle: FOXO1 , TBP2 , and PARPBP. This study suggests that RFP contributes to chemoresistance via aberrant deacetylation of histone H3 at K27, whereas dysregulation of RFP-associated cis -regulatory elements in glioma and RFP knockdown combined with temozolomide is an effective treatment strategy for lethal glioma. Graphical Abstract Highlights • RET finger protein (RFP) binds to histone deacetylase 1 in glioblastoma cells • RFP regulates H3K27acetylation and cis -regulatory elements • Knockdown of RFP modulates elements of oxidative stress and base excision repair • Knockdown of RFP overcomes chemoresistance in glioblastoma in vitro and in vivo Ranjit et al. demonstrate that the RET finger protein (RFP), which forms a complex with histone deacetylase 1 in glioma cells, also alters H3K27 acetylation patterns and cis -regulatory elements. Furthermore, RFP knockdown regulates the factors of oxidative stress and base excision repair, thereby enhancing temozolomide chemosensitivity in glioblastoma. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), the most common primary brain tumor, is the most aggressive human cancers, with a median survival rate of only 14.6 months. Temozolomide (TMZ) is the frontline chemotherapeutic drug in GBM. Drug resistance is the predominant obstacle in TMZ therapy. Drug resistance occurs via multiple pathways such as DNA mismatch repair and base excision repair systems, by which glioma cells acquire chemoresistance to some extent (5% and 95%, respectively). Histone3 Lysin27 residue-acetylation (H3K27ac) status regulates cis-regulatory elements, which increases the likelihood of gene transcription. Histone deacetylase (HDAC) complex deacetylate lysine residues on core histones, leading to a decrease in gene transcription. In cis-regulatory element regions, complexes with HDAC repress histones by H3K27ac deacetylation. The cis-regulating and three-dimensional transcriptional mechanism is called "super-enhancer". RET finger protein (RFP) is a protein that is expressed in many kinds of cancer. RFP forms a protein complex with HDAC1. The disruption of the RFP-HDAC1 complex has resulted in increased drug sensitivity in other cancers. We conclude that the downregulation of RFP or the disruption of the RFP/HDAC1 complex leads to an increase in TMZ efficacy in glioblastoma by changing histone modifications which lead to changes in cell division, cell cycle and apoptosis.

Testicular germ cell cancer is a common cancer in young adults and its incidence has risen dramatically over the past several decades in Western countries. Because RET finger protein (RFP), which belongs to the large B-box RING finger protein family, has been reported to be expressed in different stages of spermatogenesis, we investigated its expression in testicular germ cell tumors. These comprised 13 pure seminomas, five pure non-seminomatous germ cell tumors (NSGCT) and seven mixed germ cell tumors, four of which contained seminomatous component. In normal adult testis, the expression of RFP was strong in the germ cells, particularly in spermatogonia and primary spermatocytes. RFP immunoreactivity was seen uniformly and specifically in 12 of the 13 pure seminomas examined. It was also detected in seminomatous components of mixed germ cell tumors, whereas pure NSGCT were negative for RFP expression. The expression of RFP in male germ cells and seminomas together with the lack of its expression observed in highly aggressive NSGCT suggested that RFP could be associated with the regulation of germ cell proliferation and/or histological-type of germ cell tumors. [ABSTRACT FROM AUTHOR]