WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation

Kim, Jung Jin; Lee, Seung Baek; Yi, Sang Yeop; Han, Seok Joo; Kim, Sun Hyun; Lee, Jong Min; Tong, Seo Yun; Yin, Ping; Gao, Bowen; Zhang, Jun; Lou, Zhenkun

doi:10.1038/cr.2016.148

Cited by 41 publications

(33 citation statements)

References 81 publications

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“…It was found that the E3 ligase WSB1 promoted ATM ubiquitination and degradation after its activation through CDK4-mediated phosphorylation. 46 Our results establish a novel connection between CDK4/6 and ATM, which is that CDK4/6 indirectly modulates ATM levels through RPRM. We also provide another potential mechanism for the inhibition of ATM activation by CDK4/6 inhibitor Palbociclib.…”

Section: Discussionsupporting

confidence: 56%

“…MEFs were isolated as described previously. 46 Briefly, mouse embryos were harvested at E13 and the internal organs were removed, then the embryo bodies were digested using 0.25% trypsin-EDTA (Beyotime) for 30 min at 37 °C, and neutralized with DMEM containing 10% FBS. The tissue homogenate was then filtered through 40 μm nylon cell strainer (Falcon) and centrifuged at 1000 rpm for 5 min, and the pellets were resuspended and cultured in completed DMEM.…”

Section: Methodsmentioning

confidence: 99%

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RPRM negatively regulates ATM levels involving its phosphorylation mediated by CDK4/CDK6

Zhang

et al. 2021

Preprint

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Sensitizing cancer cells to radio- and chemotherapy remains a hot topic in cancer treatment. Here it is identified that Protein Reprimo (RPRM) negatively regulates the levels of ataxia-telangiectasia mutated (ATM) protein kinase, a master regulator of DNA damage response (DDR) in the presence of DNA double-strand breaks (DSBs), resulting in impaired DNA repair efficiency and enhanced cellular sensitivity to genotoxic agents. Mechanistically, although RPRM is primarily located in cytoplasm, it rapidly translocates to nucleus shortly after induced by X-irradiation, interacts with ATM and promotes the nuclear export and proteasomal degradation of ATM. The nuclear translocation of RPRM is associated with its phosphorylation at serine 98, which is mediated by cyclin-dependent kinases 4/6 (CDK4/6). Inhibition of CDK4/6 stabilizes RPRM and promotes its nuclear import, in turn enhances the nuclear export of ATM and the reduction of ATM levels. As a result, RPRM overexpression and its phosphorylation inhibition sensitize cells to genotoxic agents. Moreover, RPRM deficiency significantly increases resistance to radiation-induced damage both in vitro and in vivo. These findings establish a crucial regulatory mechanism in which ATM is negatively modulated by RPRM, suggesting that RPRM may serve as a novel target for both cancer therapy and radiation protection.

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Section: Discussionsupporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

RPRM negatively regulates ATM levels involving its phosphorylation mediated by CDK4/CDK6

Zhang

et al. 2021

Preprint

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“…Previous studies have demonstrated that mTOR signals via two distinct protein complexes termed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [7]. It is well known that the regulatory protein of mTOR, mainly Raptor, has a significant role in various kidney diseases [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Rictor Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Suppressing Autophagy and Regulating MAPK Signaling

Xu¹,

Zhu²,

Jeong³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The role of Rictor in hepatic ischemia/reperfusion (I/R) injury remains unknown. Here, we comprehensively examined the role of Rictor in hepatic I/R injury. Methods: We studied the expression of Rictor during hepatic I/R injury. The regulatory effects of Rictor on inflammatory responses, cytokine and chemokine release, apoptotic and anti-apoptotic responses, and autophagy induction during hepatic I/R injury were identified via the shRNA-mediated knockdown of Rictor. Subsequently, we collected the liver and blood samples of these mice to evaluate liver injury, mRNA and protein levels. Additionally, the signaling pathways induced by Rictor were investigated. Furthermore, the extent of activation of MAPKs in response to Rictor deficiency was investigated in lipopolysaccharide (LPS)-treated RAW264.7 cells. The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Results: The expression of Rictor was increased during hepatic I/R injury in vivo and hypoxia/reoxygenation (H/R) injury in vitro. Rictor deficiency enhanced the extent of liver injury by increasing macrophage and neutrophil infiltration, promoting cytokine and chemokine release, aggravating hepatocyte apoptosis, suppressing anti-apoptotic responses, and inhibiting autophagy induction during both hepatic I/R and H/R injury. Rictor was associated with the activation of hepatic I/R injury-induced MAPK signaling. In addition, Rictor deficiency affected MAPK activation in LPS-treated RAW264.7 cells. Conclusion: Rictor can substantially ameliorate I/R-induced liver injury. Therefore, our findings strongly suggest a therapeutic value of the Rictor/mTORC2 axis in hepatic I/R injury.

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“…On the other hand, CRL5–WSB1 has been shown to promote tumor metastasis and promote cell cycle via degrading tumor suppressors VHL, RhoGDI2, ATM, etc. ( Cao et al, 2015 ; Kim et al, 2015 , 2017 ). Therefore, the role of CRL5 E3 complexes in cancer regulation is very complicated and possibly context dependent.…”

Section: Discussionmentioning

confidence: 99%

CUL5–ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy

Gong

Wang

et al. 2021

Front. Cell Dev. Biol.

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p62/SQSTM1 (sequestosome-1) is a key protein involved in multiple cellular bioprocesses including autophagy, nutrient sensing, cell growth, cell death, and survival. Therefore, it is implicated in human diseases such as obesity and cancer. Here, we show that the CUL5–ASB6 complex is a ubiquitin E3 ligase complex mediating p62 ubiquitination and degradation. Depletion of CUL5 or ASB6 induced p62 accumulation, and overexpression of ASB6 promoted ubiquitination and degradation of p62. Functionally, ASB6 overexpression can inhibit the proliferation of MEF and hepatocellular carcinoma cells by reducing p62 protein level, and impair the occurrence of autophagy. Overall, our study identified a new molecular mechanism regulating p62 stability, which may provide additional insights for understanding the delicate control of p62 and cell proliferation–autophagy control in physiological and pathological settings.

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WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation

Cited by 41 publications

References 81 publications

RPRM negatively regulates ATM levels involving its phosphorylation mediated by CDK4/CDK6

RPRM negatively regulates ATM levels involving its phosphorylation mediated by CDK4/CDK6

Rictor Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Suppressing Autophagy and Regulating MAPK Signaling

CUL5–ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy

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