title: KR-POK interacts with p53 and represses its ability to activate transcription of p21WAF1/CDKN1A.
abstract: Transcriptional regulation by p53 is thought to play a role in its ability to suppress tumorigenesis. However, there remain gaps in understanding about how p53 regulates transcription and how disrupting this function may promote cancer. Here we report a role in these processes for the kidney cancer-related gene KR-POK (ZBTB7C), a POZ domain and Krüppel-like zinc finger transcription factor that we found to physically interact with p53. Murine embryonic fibroblasts isolated from genetically deficient mice (Kr-pok(-/-) MEFs) exhibited a proliferative defect relative to wild-type mouse embryonic fibroblasts (MEF). The zinc finger domain of Kr-pok interacted directly with the DNA binding and oligomerization domains of p53. This interaction was essential for Kr-pok to bind the distal promoter region of the CDKN1A gene, an important p53 target gene encoding the cell-cycle regulator p21WAF1, and to inhibit p53-mediated transcriptional activation of CDKN1A. Kr-pok also interacted with the transcriptional corepressors NCoR and BCoR, acting to repress histone H3 and H4 deacetylation at the proximal promoter region of the CDKN1A gene. Importantly, Kr-pok(-/-) MEFs displayed an enhancement in CDKN1A transactivation by p53 during the DNA damage response, without any parallel changes in transcription of either the p53 or Kr-pok genes themselves. Furthermore, Kr-pok promoted cell proliferation in vitro and in vivo, and its expression was increased in more than 50% of the malignant human kidney cancer cases analyzed. Together, our findings define KR-POK as a transcriptional repressor with a pro-oncogenic role that relies upon binding to p53 and inhibition of its transactivation function.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Severance Institute of Biomedical Science, Seoul, Korea.
authors.forename: Bu-Nam
authors.initials: BN
authors.lastname: Jeon
authors.forename: Min-Kyeong
authors.initials: MK
authors.lastname: Kim
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koh
authors.forename: Sung-Yi
authors.initials: SY
authors.lastname: Hong
authors.forename: Kyung-Sup
authors.initials: KS
authors.lastname: Kim
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
authors.forename: Juyong
authors.initials: J
authors.lastname: Yoon
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.forename: Kyung-Ryul
authors.initials: KR
authors.lastname: Lee
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D016335:Zinc Fingers
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C110461:ZBTB7C protein, human