Search

Your search keyword '"Wenjian Gan"' showing total 2 results
Start Over Author "Wenjian Gan" Journal molecular cell
2 results on '"Wenjian Gan"'

1. SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression

Author

John M. Asara, Jinfang Zhang, Wenyi Wei, Jiaoti Huang, Hiroyuki Inuzuka, Xiangpeng Dai, Shoreh Varmeh, Pier Paolo Pandolfi, Liang Cheng, Zhen Li, Andrea Lunardi, Yin Sun, Pengda Liu, Wenjian Gan, and Andrew H. Beck

Subjects
Male, genetic structures, Amino Acid Sequence, Antineoplastic Agents, Phytogenic, Cell Line, Tumor, Cell Movement, Cullin Proteins, Disease Progression, Etoposide, HEK293 Cells, Humans, Molecular Sequence Data, Neoplasm Invasiveness, Nuclear Proteins, Prostatic Neoplasms, Protein Interaction Domains and Motifs, Proteolysis, Repressor Proteins, Trans-Activators, Tumor Suppressor Proteins, Ubiquitination, Molecular Biology, Cell Biology, Antineoplastic Agents, SPOP, TMPRSS2, Article, Cell Line, Fusion gene, Transcriptional Regulator ERG, Ubiquitin, Phytogenic, Tumor, biology, Molecular biology, eye diseases, Ubiquitin ligase, biology.protein, Cancer research, sense organs, Erg, Cullin
Abstract

The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.

Published
2015
Full Text
View/download PDF

2. Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt

Author

Jianping Guo, Kai Xu, Wenjian Gan, Jinfang Zhang, Christian Berrios, Alex Toker, Piotr Sicinski, Fei Wu, Evan C. Lien, Yan Geng, James A. DeCaprio, Y. Rebecca Chin, Pengda Liu, Wenyi Wei, and Bin Wang

Subjects
0301 basic medicine, Time Factors, Cyclin D, mTORC1, mTORC2, Retinoblastoma Protein, Mice, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Molecular Targeted Therapy, Phosphorylation, TOR Serine-Threonine Kinases, Drug Synergism, 3. Good health, RNA Interference, Signal transduction, biological phenomena, cell phenomena, and immunity, Protein Binding, Signal Transduction, Mechanistic Target of Rapamycin Complex 2, Biology, Transfection, Article, 03 medical and health sciences, Enzyme activator, Animals, Humans, Protein Interaction Domains and Motifs, Molecular Biology, Protein kinase B, Transcription factor, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Cell Proliferation, Dose-Response Relationship, Drug, Cyclin-Dependent Kinase 4, Cell Biology, Cyclin-Dependent Kinase 6, HCT116 Cells, Enzyme Activation, 030104 developmental biology, HEK293 Cells, Drug Resistance, Neoplasm, Multiprotein Complexes, Cancer research, biology.protein, Proto-Oncogene Proteins c-akt, HeLa Cells
Abstract

The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell cycle progression. However, it remains largely elusive whether hyper-phosphorylated, non-E2F1-interacting form, of Rb has any physiological role. Here, we report that hyper-phosphorylated Rb directly binds to, and suppresses the function of mTORC2, but not mTORC1. Mechanistically, Rb, but not p107 nor p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D, or using CDK4/6 inhibitors, releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer.

Published
2015

Catalog

Books, media, physical & digital resources
See catalog results