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p53 Stabilization and Transactivation by a von Hippel-Lindau Protein
Roe, Jae-Seok,Kim, Hyungsoo,Lee, Soon-Min,Kim, Sung-Tae,Cho, Eun-Jung,Youn, Hong-Duk Elsevier 2006 Molecular cell Vol.22 No.3
<P><B>Summary</B></P><P>von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. Although hypoxia-inducible factor-α (HIFα) is a well-documented substrate of von Hippel-Lindau tumor suppressor protein (pVHL), it remains unclear whether the dysregulation of HIF is sufficient to account for de novo tumorigenesis in VHL-deleted cells. Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53. Moreover, upon genotoxic stress, pVHL invoked an interaction between p53 and p300 and the acetylation of p53, which ultimately led to an increase in p53 transcriptional activity and p53-mediated cell cycle arrest and apoptosis. These results suggest that the tumor suppressor pVHL has an unexpected function to upregulate the tumor suppressor p53.</P>
The Positive Regulation of p53 by the Tumor Suppressor VHL
Roe, Jae-Seok,Youn, Hong-Duk Informa UK (TaylorFrancis) 2006 Cell cycle Vol.5 No.18
<P>The ubiquitin-mediated degradation of hypoxia-inducible factor-alpha (HIF-alpha) by a von Hippel-Lindau tumor suppressor protein (pVHL) is mechanistically responsible for controlling gene expression due to oxygen availability. Germline mutations in the VHL gene cause dysregulation of HIF and induce an autosomal dominant cancer syndrome referred to as VHL disease. However, it is unclear whether HIF accumulation caused by VHL mutations is sufficient for tumorigenesis. Recently, we found that pVHL directly associates and positively regulates the tumor suppressor p53 by inhibiting Mdm2-mediated ubiquitination, and by subsequently recruiting p53-modifying enzymes. Moreover, VHL-deleted RCC cells showed attenuated apoptosis or abnormal cell-cycle arrest upon DNA damage, but became normal when pVHL was restored. Thus, pVHL appears to play a pivotal role in tumor suppression by participating actively as a component of p53 transactivation complex during DNA damage response.</P>
Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation.
Roe, Jae-Seok,Kim, Hwa-Ryeon,Hwang, In-Young,Ha, Nam-Chul,Kim, Seong-Tae,Cho, Eun-Jung,Youn, Hong-Duk Landes Bioscience 2011 Cell Cycle Vol.10 No.22
<P>von-Hippel Lindau protein (pVHL) suppresses tumorigenesis in the kidney, in part through regulation of hypoxia-inducible factor alpha (HIF alpha). However, HIF has been proposed to be necessary but insufficient for renal tumorigenesis. p53 was implicated as a transcription factor that is regulated by pVHL, but the molecular mechanism by which pVHL regulates p53 on DNA damage is unknown. We demonstrated that checkpoint kinase-2 (Chk2) binds to the beta-domain of pVHL and phosphorylates Ser 111 on DNA damage. Notably, this modification enhances pVHL-mediated transactivation of p53 by recruiting p300 and Tip60 to the chromatin of p53 target gene. Further, the naturally occurring pVHL mutants pVHL-S111R and pVHL-S111C showed diminished binding to coactivators, ultimately retarding p53-mediated growth arrest and apoptosis. In this study, we determined the molecular mechanism by which pVHL transactivates p53 on DNA damage and demonstrated that p53-related pVHL subtype mutants regulate tumorigenecity in VHL diseases.</P>
p53 STABILIZATION AND TRANSACTIVATION BY A VON HIPPEL-LINDAU PROTEIN
Roe, Jae-Seok,Kim, Hyungsoo,Lee, Soon-Min,Youn, Hong-Duk 이화여자대학교 세포신호전달연구센터 2006 고사리 세포신호전달 심포지움 Vol. No.8
von Hippel-Lindau(VHL) disease is a rare autosomal dominant cancer syndrome. Although hypoxia inducible factor-α(HIF-α) is a well-documented substrate of a von Hippel-Lindau tumor suppressor protein(pVHL), it remains controversial as to whether the dysregulation of HIF is sufficient for de novo tumorigenesis in VHL-deleted cells, which suggests that pVHL may have HIF-independent tumor suppressor functions. Here we found that pVHL directly associates with and stabilizes p53 by suppressing the mdm2-mediated ubiquitination and nuclear export of p53. Moreover, upon genotoxic stress, pVHL invoked a synergistic interaction between p53 and p300, and thus the acetylation of p53, which ultimately led to increasing p53 transcriptional activity and p53-mediated cell cycle arrest and apoptosis. This mechanism suggests that the tumor suppressor pVHL has an unexpected function to upregulate another tumor suppressor p53.
Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death
( Soohyun Lee ),( Yoonjeong Jeong ),( Jae-seok Roe ),( Hoyoung Huh ),( Sang Hoon Paik ),( Jaewhan Song ) 생화학분자생물학회(구 한국생화학분자생물학회) 2021 BMB Reports Vol.54 No.4
Callyspongiolide is a marine macrolide known to induce caspaseindependent cancer cell death. While its toxic effects have been known, the mechanism leading to cell death is yet to be identified. We report that Callyspongiolide R form at C-21 (cally2R) causes mitochondrial dysfunction by inhibiting mitochondrial complex I or II, leading to a disruption of mitochondrial membrane potential and a deprivation of cellular energy. Subsequently, we observed, using electron microscopy, a drastic formation of autophagosome and mitophagy. Supporting these data, LC3, an autophagosome marker, was shown to co-localize with LAMP2, a lysosomal protein, showing autolysosome formation. RNA sequencing results indicated the induction of hypoxia and blocking of EGF-dependent pathways, which could be caused by induction of autophagy. Furthermore, mTOR and AKT pathways preventing autophagy were repressed while AMPK was upregulated, supporting autophagosome progress. Finally, the combination of cally2R with known anti-cancer drugs, such as gefitinib, sorafenib, and rapamycin, led to synergistic cell death, implicating potential therapeutic applications of callyspongiolide for future treatments. [BMB Reports 2021; 54(4): 227-232]
pVHL-Mediated Transcriptional Repression of c-Myc by Recruitment of Histone Deacetylases
황인영,윤홍덕,조은정,Jae-Seok Roe,설자환,김화연 한국분자세포생물학회 2012 Molecules and cells Vol.33 No.2
The biological functions of Myc are to regulate cell growth, apoptosis, cell differentiation and stem-cell self-renewal. Abnormal accumulation of c-Myc is able to induce excessive proliferation of normal cells. von Hippel-Lindau protein (pVHL) is a key regulator of hypoxia-inducible factor1 (HIF1), thus accumulation and hyperactivation of HIF1 is the most prominent feature of VHL-mutated renal cell carcinoma. Interestingly, the Myc pathway is reported to be activated in renal cell carcinoma even though the precise molecular mechanism still remains to be established. Here, we demonstrated that pVHL locates at the c-Myc promoter region through physical interaction with Myc. Furthermore, pVHL reinforces HDAC1/2 recruitment to the Myc promoter, which leads to the auto-suppression of Myc. Therefore, one possible mechanism of Myc auto-suppression by pVHL entails removing histone acetylation. Our study identifies a novel mechanism for pVHL-mediated negative regulation of c-Myc transcription.
Choi, Soo-Youn,Jang, Hyonchol,Roe, Jae-Seok,Kim, Seong-Tae,Cho, Eun-Jung,Youn, Hong-Duk Oxford University Press 2013 Nucleic acids research Vol.41 No.4
<P>CABIN1 acts as a negative regulator of p53 by keeping p53 in an inactive state on chromatin. Genotoxic stress causes rapid dissociation of CABIN1 and activation of p53. However, its molecular mechanism is still unknown. Here, we reveal the phosphorylation- and ubiquitination-dependent degradation of CABIN1 upon DNA damage, releasing p53 for transcriptional activation. The DNA-damage-signaling kinases, ATM and CHK2, phosphorylate CABIN1 and increase the degradation of CABIN1 protein. Knockdown or overexpression of these kinases influences the stability of CABIN1 protein showing that their activity is critical for degradation of CABIN1. Additionally, CABIN1 was found to undergo ubiquitin-dependent proteasomal degradation mediated by the CRL4DDB2 ubiquitin ligase complex. Both phosphorylation and ubiquitination of CABIN1 appear to be relevant for controlling the level of CABIN1 protein upon genotoxic stress.</P>