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1,032 results on '"Ronai, Ze'ev A."'

207. SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Author

Tamiya, Hironari, primary, Kim, Hyungsoo, additional, Klymenko, Oleksiy, additional, Kim, Heejung, additional, Feng, Yongmei, additional, Zhang, Tongwu, additional, Han, Ji Yun, additional, Murao, Ayako, additional, Snipas, Scott J., additional, Jilaveanu, Lucia, additional, Brown, Kevin, additional, Kluger, Harriet, additional, Zhang, Hao, additional, Iwai, Kazuhiro, additional, and Ronai, Ze’ev A., additional

Published
2017
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208. The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and aldosterone secretion

Author

Scortegagna, Marzia, primary, Berthon, Annabel, additional, Settas, Nikolaos, additional, Giannakou, Andreas, additional, Garcia, Guillermina, additional, Li, Jian-Liang, additional, James, Brian, additional, Liddington, Robert C., additional, Vilches-Moure, José G., additional, Stratakis, Constantine A., additional, and Ronai, Ze’ev A., additional

Published
2017
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210. Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons.

Author

Welsbie, Derek S, Welsbie, Derek S, Mitchell, Katherine L, Jaskula-Ranga, Vinod, Sluch, Valentin M, Yang, Zhiyong, Kim, Jessica, Buehler, Eugen, Patel, Amit, Martin, Scott E, Zhang, Ping-Wu, Ge, Yan, Duan, Yukan, Fuller, John, Kim, Byung-Jin, Hamed, Eman, Chamling, Xitiz, Lei, Lei, Fraser, Iain DC, Ronai, Ze'ev A, Berlinicke, Cynthia A, Zack, Donald J, Welsbie, Derek S, Welsbie, Derek S, Mitchell, Katherine L, Jaskula-Ranga, Vinod, Sluch, Valentin M, Yang, Zhiyong, Kim, Jessica, Buehler, Eugen, Patel, Amit, Martin, Scott E, Zhang, Ping-Wu, Ge, Yan, Duan, Yukan, Fuller, John, Kim, Byung-Jin, Hamed, Eman, Chamling, Xitiz, Lei, Lei, Fraser, Iain DC, Ronai, Ze'ev A, Berlinicke, Cynthia A, and Zack, Donald J

Abstract

Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases.

Published
2017

211. Lipid metabolism: new twists to the Yin and Yang of PKM2 in cancer.

Author

Khateb, Ali and Ronai, Ze'ev A

Subjects
*LIPID metabolism, *HOMEOSTASIS, *MEMBRANE proteins, *CELL metabolism, *CELLULAR control mechanisms, *CHOLESTEROL metabolism, *PYRUVATE kinase
Abstract

While canonical and non‐canonical functions of pyruvate kinase M2 (PKM2) are recognized to mediate often‐opposing roles in cancer, its contribution to cellular and systemic fatty acid homeostasis remains poorly understood. A new study by Liu et al (2021) uncovers ER transmembrane protein TMEM33 as a novel target of PKM2, which is essential for regulation of cancer cell cholesterol metabolism. These findings highlight the diversity of tissue‐specific functions of PKM2 and potential implications for cancer treatment. [ABSTRACT FROM AUTHOR]

Published
2021
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213. Regulation of eIF2α by RNF4 Promotes Melanoma Tumorigenesis and Therapy Resistance

Author

Avitan-Hersh, Emily, Feng, Yongmei, Oknin Vaisman, Avital, Abu Ahmad, Yamen, Zohar, Yaniv, Zhang, Tongwu, Lee, Joo Sang, Lazar, Ikrame, Sheikh Khalil, Saeed, Feiler, Yulia, Kluger, Harriet, Kahana, Chaim, Brown, Kevin, Ruppin, Eytan, Ronai, Ze’ev A., and Orian, Amir

Abstract

Among the hallmarks of melanoma are impaired proteostasis and rapid development of resistance to targeted therapy that represent a major clinical challenge. However, the molecular machinery that links these processes is unknown. Here we describe that by stabilizing key melanoma oncoproteins, the ubiquitin ligase RNF4 promotes tumorigenesis and confers resistance to targeted therapy in melanoma cells, xenograft mouse models, and patient samples. In patients, RNF4 protein and mRNA levels correlate with poor prognosis and with resistance to MAPK inhibitors. Remarkably, RNF4 tumorigenic properties, including therapy resistance, require the translation initiation factor initiation elongation factor alpha (eIF2α). RNF4 binds, ubiquitinates, and stabilizes the phosphorylated eIF2α (p-eIF2α) but not activating transcription factor 4 or C/EBP homologous protein that mediates the eIF2α−dependent integrated stress response. In accordance, p-eIF2α levels were significantly elevated in high-RNF4 patient-derived melanomas. Thus, RNF4 and p-eIF2α establish a positive feed-forward loop connecting oncogenic translation and ubiquitin-dependent protein stabilization in melanoma.

Published
2020
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216. Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons

Author

Welsbie, Derek S., primary, Mitchell, Katherine L., additional, Jaskula-Ranga, Vinod, additional, Sluch, Valentin M., additional, Yang, Zhiyong, additional, Kim, Jessica, additional, Buehler, Eugen, additional, Patel, Amit, additional, Martin, Scott E., additional, Zhang, Ping-Wu, additional, Ge, Yan, additional, Duan, Yukan, additional, Fuller, John, additional, Kim, Byung-Jin, additional, Hamed, Eman, additional, Chamling, Xitiz, additional, Lei, Lei, additional, Fraser, Iain D.C., additional, Ronai, Ze’ev A., additional, Berlinicke, Cynthia A., additional, and Zack, Donald J., additional

Published
2017
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219. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

Author

Falletta, Paola, primary, Sanchez-del-Campo, Luis, additional, Chauhan, Jagat, additional, Effern, Maike, additional, Kenyon, Amy, additional, Kershaw, Christopher J., additional, Siddaway, Robert, additional, Lisle, Richard, additional, Freter, Rasmus, additional, Daniels, Matthew J., additional, Lu, Xin, additional, Tüting, Thomas, additional, Middleton, Mark, additional, Buffa, Francesca M., additional, Willis, Anne E., additional, Pavitt, Graham, additional, Ronai, Ze'ev A., additional, Sauka-Spengler, Tatjana, additional, Hölzel, Michael, additional, and Goding, Colin R., additional

Published
2017
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220. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1 alpha abundance, and modulates physiological responses to hypoxia

Author

Nakayama, Koh, Ronai, Ze'ev, Bowtell, David D., Frappell, Peter B., Tempst, Paul, Frew, Ian J., Hagensen, Mette, Skals, Marianne, Habelhah, Hasem, Erdjument-Bromage, Hediye, Kadoya, Takayuki, and Bhoumik, Anindita

Subjects
Ubiquitin -- Research, Gene expression -- Research, Hypoxia -- Research, Biological sciences
Abstract

The novel mechanism underlying the increase in hypoxia-inducible factor-1 (HIF1) alpha expression during hypoxic conditions is examined. The regulation of abundance of prolyl hydroxylase domain 1(PHD1) and prolyl hydroxylase domain 3 (PHD3) via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases Siah 1a/2 is demonstrated under hypoxia conditions.

Published
2004

221. Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities

Author

Khateb, Ali and Ronai, Ze’ev A.

Abstract

Understanding genetic and epigenetic changes that underlie abnormal proliferation of hematopoietic stem and progenitor cells is critical for development of new approaches to monitor and treat leukemia. The unfolded protein response (UPR) is a conserved adaptive signaling pathway that governs protein folding, secretion, and energy production and serves to maintain protein homeostasis in various cellular compartments. Deregulated UPR signaling, which often occurs in hematopoietic stem cells and leukemia, defines the degree of cellular toxicity and perturbs protein homeostasis, and at the same time, offers a novel therapeutic target. Here, we review current knowledge related to altered UPR signaling in leukemia and highlight possible strategies for exploiting the UPR as treatment for this disease.

Published
2020
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222. Translational reprogramming marks adaptation to asparagine restriction in cancer

Author

Pathria, Gaurav, Lee, Joo Sang, Hasnis, Erez, Tandoc, Kristofferson, Scott, David A., Verma, Sachin, Feng, Yongmei, Larue, Lionel, Sahu, Avinash D., Topisirovic, Ivan, Ruppin, Eytan, and Ronai, Ze’ev A.

Abstract

While amino acid restriction remains an attractive strategy for cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted cancer cells. Asparagine limitation in melanoma and pancreatic cancer cells activates receptor tyrosine kinase–MAPK signalling as part of a feedforward mechanism involving mammalian target of rapamycin complex 1 (mTORC1)-dependent increase in MAPK-interacting kinase 1 (MNK1) and eukaryotic translation initiation factor 4E (eIF4E), resulting in enhanced translation of activating transcription factor 4 (ATF4) mRNA. MAPK inhibition attenuates translational induction of ATF4 and the expression of its target asparagine synthetase (ASNS), sensitizing melanoma and pancreatic tumours to asparagine restriction, reflected in inhibition of their growth. Correspondingly, low ASNSexpression is among the top predictors of response to inhibitors of MAPK signalling in patients with melanoma and is associated with favourable prognosis when combined with low MAPK signalling activity. These studies reveal an axis of adaptation to asparagine deprivation and present a rationale for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches.

Published
2019
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223. SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation.

Author

Tian-Xia Jiang, Jiang-Bo Zou, Qian-Qian Zhu, Cui Hua Liu, Guang-Fei Wang, Ting-Ting Du, Zi-Yu Luo, Fang Guo, Lu-Ming Zhou, Juan-Juan Liu, Wensheng Zhang, You-Sheng Shu, Li Yu, Peng Li, Ronai, Ze'ev A., Shu-ichi Matsuzawa, Goldberg, Alfred L., and Xiao-Bo Qiu

Subjects
DNA topoisomerase inhibitors, MITOCHONDRIAL proteins, PROTEASOMES
Abstract

BRUCE/Apollon is a membrane-associated inhibitor of apoptosis protein that is essential for viability and has ubiquitin-conjugating activity. On initiation of apoptosis, the ubiquitin ligase Nrdp1/RNF41 promotes proteasomal degradation of BRUCE. Here we demonstrate that BRUCE together with the proteasome activator PA28γ causes proteasomal degradation of LC3-I and thus inhibits autophagy. LC3-I on the phagophore membrane is conjugated to phosphatidylethanol-amine to form LC3-II, which is required for the formation of autophagosomes and selective recruitment of substrates. SIP/CacyBP is a ubiquitination-related protein that is highly expressed in neurons and various tumors. Under normal conditions, SIP inhibits the ubiquitination and degradation of BRUCE, probably by blocking the binding of Nrdp1 to BRUCE. On DNA damage by topoisomerase inhibitors, Nrdp1 causes monoubiquitination of SIP and thus promotes apoptosis. However, on starvation, SIP together with Rab8 enhances the translocation of BRUCE into the recycling endosome, formation of autophagosomes, and degradation of BRUCE by optineurin-mediated autophagy. Accordingly, deletion of SIP in cultured cells reduces the autophagic degradation of damaged mitochondria and cytosolic protein aggregates. Thus, by stimulating proteasomal degradation of LC3-I, BRUCE also inhibits autophagy. Conversely, SIP promotes autophagy by blocking BRUCE-dependent degradation of LC3-I and by enhancing autophagosome formation and autophagic destruction of BRUCE. These actions of BRUCE and SIP represent mechanisms that link the regulation of autophagy and apoptosis under different conditions. [ABSTRACT FROM AUTHOR]

Published
2019
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224. The state of melanoma: challenges and opportunities.

Author

Merlino, Glenn, Merlino, Glenn, Herlyn, Meenhard, Fisher, David E, Bastian, Boris C, Flaherty, Keith T, Davies, Michael A, Wargo, Jennifer A, Curiel-Lewandrowski, Clara, Weber, Michael J, Leachman, Sancy A, Soengas, Maria S, McMahon, Martin, Harbour, J William, Swetter, Susan M, Aplin, Andrew E, Atkins, Michael B, Bosenberg, Marcus W, Dummer, Reinhard, Gershenwald, Jeffrey E, Halpern, Allan C, Herlyn, Dorothee, Karakousis, Giorgos C, Kirkwood, John M, Krauthammer, Michael, Lo, Roger S, Long, Georgina V, McArthur, Grant, Ribas, Antoni, Schuchter, Lynn, Sosman, Jeffrey A, Smalley, Keiran S, Steeg, Patricia, Thomas, Nancy E, Tsao, Hensin, Tueting, Thomas, Weeraratna, Ashani, Xu, George, Lomax, Randy, Martin, Alison, Silverstein, Steve, Turnham, Tim, Ronai, Ze'ev A, Merlino, Glenn, Merlino, Glenn, Herlyn, Meenhard, Fisher, David E, Bastian, Boris C, Flaherty, Keith T, Davies, Michael A, Wargo, Jennifer A, Curiel-Lewandrowski, Clara, Weber, Michael J, Leachman, Sancy A, Soengas, Maria S, McMahon, Martin, Harbour, J William, Swetter, Susan M, Aplin, Andrew E, Atkins, Michael B, Bosenberg, Marcus W, Dummer, Reinhard, Gershenwald, Jeffrey E, Halpern, Allan C, Herlyn, Dorothee, Karakousis, Giorgos C, Kirkwood, John M, Krauthammer, Michael, Lo, Roger S, Long, Georgina V, McArthur, Grant, Ribas, Antoni, Schuchter, Lynn, Sosman, Jeffrey A, Smalley, Keiran S, Steeg, Patricia, Thomas, Nancy E, Tsao, Hensin, Tueting, Thomas, Weeraratna, Ashani, Xu, George, Lomax, Randy, Martin, Alison, Silverstein, Steve, Turnham, Tim, and Ronai, Ze'ev A

Abstract

The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and long-term needs of the melanoma field, from basic research to clinical management, are presented in the following report.

Published
2016

228. A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis

Author

Claps, Giuseppina, primary, Cheli, Yann, additional, Zhang, Tongwu, additional, Scortegagna, Marzia, additional, Lau, Eric, additional, Kim, Hyungsoo, additional, Qi, Jianfei, additional, Li, Jian-Liang, additional, James, Brian, additional, Dzung, Andreas, additional, Levesque, Mitchell P., additional, Dummer, Reinhard, additional, Hayward, Nicholas K., additional, Bosenberg, Marcus, additional, Brown, Kevin M., additional, and Ronai, Ze’ev A., additional

Published
2016
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229. The state of melanoma: challenges and opportunities

Author

Merlino, Glenn, primary, Herlyn, Meenhard, additional, Fisher, David E., additional, Bastian, Boris C., additional, Flaherty, Keith T., additional, Davies, Michael A., additional, Wargo, Jennifer A., additional, Curiel‐Lewandrowski, Clara, additional, Weber, Michael J., additional, Leachman, Sancy A., additional, Soengas, Maria S., additional, McMahon, Martin, additional, Harbour, J. William, additional, Swetter, Susan M., additional, Aplin, Andrew E., additional, Atkins, Michael B., additional, Bosenberg, Marcus W., additional, Dummer, Reinhard, additional, Gershenwald, Jeffrey E., additional, Halpern, Allan C., additional, Herlyn, Dorothee, additional, Karakousis, Giorgos C., additional, Kirkwood, John M., additional, Krauthammer, Michael, additional, Lo, Roger S., additional, Long, Georgina V., additional, McArthur, Grant, additional, Ribas, Antoni, additional, Schuchter, Lynn, additional, Sosman, Jeffrey A., additional, Smalley, Keiran S., additional, Steeg, Patricia, additional, Thomas, Nancy E., additional, Tsao, Hensin, additional, Tueting, Thomas, additional, Weeraratna, Ashani, additional, Xu, George, additional, Lomax, Randy, additional, Martin, Alison, additional, Silverstein, Steve, additional, Turnham, Tim, additional, and Ronai, Ze'ev A., additional

Published
2016
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233. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies.

Author

Jeon, Young Joo, Jeon, Young Joo, Khelifa, Sihem, Ratnikov, Boris, Scott, David A, Feng, Yongmei, Parisi, Fabio, Ruller, Chelsea, Lau, Eric, Kim, Hyungsoo, Brill, Laurence M, Jiang, Tingting, Rimm, David L, Cardiff, Robert D, Mills, Gordon B, Smith, Jeffrey W, Osterman, Andrei L, Kluger, Yuval, Ronai, Ze'ev A, Jeon, Young Joo, Jeon, Young Joo, Khelifa, Sihem, Ratnikov, Boris, Scott, David A, Feng, Yongmei, Parisi, Fabio, Ruller, Chelsea, Lau, Eric, Kim, Hyungsoo, Brill, Laurence M, Jiang, Tingting, Rimm, David L, Cardiff, Robert D, Mills, Gordon B, Smith, Jeffrey W, Osterman, Andrei L, Kluger, Yuval, and Ronai, Ze'ev A

Abstract

Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

Published
2015

234. Downregulation of the ubiquitin ligase RNF125 underlies resistance of melanoma cells to BRAF inhibitors via JAK1 deregulation

Author

Kim, Hyungsoo, Frederick, Dennie T, Levesque, Mitchell P, Cooper, Zachary A, Feng, Yongmei, Krepler, Clemens, Brill, Laurence, Samuels, Yardena, Hayward, Nicholas K, Perlina, Ally, Piris, Adriano, Zhang, Tongwu, Halaban, Ruth, Herlyn, Meenhard M, Brown, Kevin M, Wargo, Jennifer A, Dummer, Reinhard, Flaherty, Keith T, Ronai, Ze'ev A, Kim, Hyungsoo, Frederick, Dennie T, Levesque, Mitchell P, Cooper, Zachary A, Feng, Yongmei, Krepler, Clemens, Brill, Laurence, Samuels, Yardena, Hayward, Nicholas K, Perlina, Ally, Piris, Adriano, Zhang, Tongwu, Halaban, Ruth, Herlyn, Meenhard M, Brown, Kevin M, Wargo, Jennifer A, Dummer, Reinhard, Flaherty, Keith T, and Ronai, Ze'ev A

Abstract

Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression.

Published
2015

237. SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex

Author

Feng, Yongmei, primary, Pinkerton, Anthony B., additional, Hulea, Laura, additional, Zhang, Tongwu, additional, Davies, Michael A., additional, Grotegut, Stefan, additional, Cheli, Yann, additional, Yin, Hongwei, additional, Lau, Eric, additional, Kim, Hyungsoo, additional, De, Surya K., additional, Barile, Elisa, additional, Pellecchia, Maurizio, additional, Bosenberg, Marcus, additional, Li, Jian-Liang, additional, James, Brian, additional, Hassig, Christian A., additional, Brown, Kevin M., additional, Topisirovic, Ivan, additional, and Ronai, Ze'ev A., additional

Published
2015
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240. Effective inhibition of melanoma by BI-69A11 is mediated by dual targeting of the AKT and NF-κB pathways

Author

Feng, Yongmei, Barile, Elisa, De, Surya K., Stebbins, John L., Cortez, Apple, Aza-Blanc, Pedro, Villanueva, Jessie, Heryln, Meenhard, Krajewski, Stan, Pellecchia, Maurizio, Ronai, Ze’ev A., and Chiang, Gary G.

Subjects
Proto-Oncogene Proteins B-raf, Skin Neoplasms, NF-kappa B, Administration, Oral, Mice, Nude, Quinolones, Xenograft Model Antitumor Assays, Article, Mice, Phosphotransferases (Alcohol Group Acceptor), Drug Resistance, Neoplasm, Cell Line, Tumor, Animals, Humans, Benzimidazoles, Molecular Targeted Therapy, Melanoma, Proto-Oncogene Proteins c-akt, Cell Proliferation, Signal Transduction
Abstract

In melanoma, the activation of pro-survival signaling pathways, such as the AKT and NF-κB pathways, is critical for tumor growth. We have recently reported that the AKT inhibitor BI-69A11 causes efficient inhibition of melanoma growth. Here, we show that in addition to its AKT inhibitory activity, BI-69A11 also targets the NF-κB pathway. In melanoma cell lines, BI-69A11 inhibited TNF-α-stimulated IKKα/β and IκB phosphorylation as well as NF-κB reporter gene expression. Furthermore, the effective inhibition of melanoma growth by BI-69A11 was attenuated upon NF-κB activation. Mechanistically, reduced NF-κB signaling by BI-69-A11 is mediated by the inhibition of sphingosine kinase 1, identified in a screen of 315 kinases. Significantly, we demonstrate that BI-69A11 is well tolerated and orally active against UACC 903 and SW1 melanoma xenografts. Our results demonstrate that BI-69A11 inhibits both the AKT and the NF-κB pathways and that the dual targeting of these pathways may be efficacious as a therapeutic strategy in melanoma.

Published
2011

244. Genetic Inhibition Of The Ubiquitin Ligase Rnf5 Attenuates Phenotypes Associated To F508del Cystic Fibrosis Mutation

Author

Tomati, Valeria, primary, Sondo, Elvira, additional, Armirotti, Andrea, additional, Caci, Emanuela, additional, Pesce, Emanuela, additional, Marini, Monica, additional, Gianotti, Ambra, additional, Ju Jeon, Young, additional, Cilli, Michele, additional, Pistorio, Angela, additional, Mastracci, Luca, additional, Ravazzolo, Roberto, additional, Scholte, Bob, additional, Ronai, Ze’ev, additional, Galietta, Luis J. V., additional, and Pedemonte, Nicoletta, additional

Published
2015
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245. Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation

Author

Kim, Hyungsoo, primary, Frederick, Dennie T., additional, Levesque, Mitchell P., additional, Cooper, Zachary A., additional, Feng, Yongmei, additional, Krepler, Clemens, additional, Brill, Laurence, additional, Samuels, Yardena, additional, Hayward, Nicholas K., additional, Perlina, Ally, additional, Piris, Adriano, additional, Zhang, Tongwu, additional, Halaban, Ruth, additional, Herlyn, Meenhard M., additional, Brown, Kevin M., additional, Wargo, Jennifer A., additional, Dummer, Reinhard, additional, Flaherty, Keith T., additional, and Ronai, Ze’ev A., additional

Published
2015
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249. PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets

Author

Scortegagna, Marzia, primary, Lau, Eric, additional, Zhang, Tongwu, additional, Feng, Yongmei, additional, Sereduk, Chris, additional, Yin, Hongwei, additional, De, Surya K., additional, Meeth, Katrina, additional, Platt, James T., additional, Langdon, Casey G., additional, Halaban, Ruth, additional, Pellecchia, Maurizio, additional, Davies, Michael A., additional, Brown, Kevin, additional, Stern, David F., additional, Bosenberg, Marcus, additional, and Ronai, Ze'ev A., additional

Published
2015
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