Identification of ANKRD11 as a p53 coactivator.
The ability of p53 to act as a transcription factor is critical for its function as a tumor suppressor. Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. ANKRD11 expression was shown to be downregulated in breast cancer cell lines. Restoration of ANKRD11 expression in MCF-7 (wild-type p53) and MDA-MB-468 (p53(R273H) mutant) cells suppressed their proliferative and clonogenic properties through enhancement of CDKN1A (p21(waf1)/CIP1) expression. ShRNA-mediated silencing of ANKRD11 expression reduced the ability of p53 to activate CDKN1A expression. ANKRD11 was shown to associate with the p53 acetyltransferases and cofactors, P/CAF and hADA3. Exogenous ANKRD11 expression enhanced the levels of acetylated p53 in both MCF-7 and MDA-MB-468 cells. ANKRD11 enhanced the DNA-binding properties of mutant p53(R273H) to the CDKN1A promoter, suggesting that ANKRD11 can mediate the restoration of normal p53 function in some cancer-related p53 mutations. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.
Breast Cancer Genetics Group, Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide and Hanson Institute, IMVS, Adelaide, SA 5000, Australia. Paul.Neilsen@imvs.sa.gov.au
Paul M
PM
Neilsen
Kelly M
KM
Cheney
Chia-Wei
CW
Li
J Don
JD
Chen
Jacqueline E
JE
Cawrse
Renée B
RB
Schulz
Jason A
JA
Powell
Raman
R
Kumar
David F
DF
Callen
D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C492515:ANKRD11 protein, human; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA