Open AccessCARF (Collaborator of ARF) overexpression in p53‐deficient cells promotes carcinogenesis
Author(s) -
Kalra Rajkumar S.,
Cheung Caroline T.,
Chaudhary Anupama,
Prakash Jay,
Kaul Sunil C.,
Wadhwa Renu
Publication year - 2015
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2015.07.003
Subject(s) - carcinogenesis , downregulation and upregulation , cancer research , cancer cell , chemistry , signal transduction , cell growth , cyclin dependent kinase 6 , apoptosis , cell cycle checkpoint , p14arf , microbiology and biotechnology , gene knockdown , cancer , cell cycle , biology , tumor suppressor gene , biochemistry , cyclin d1 , gene , genetics
Collaborator of ARF (CARF), initially identified as a binding partner of ARF (Alternate Reading Frame), has been shown to activate ARF–p53 pathway by multiple ways including stabilization of ARF and p53 tumor suppressor proteins, and transcriptional repression of a p53 antagonist, HDM2. Level of CARF expression was shown to determine fate of cells. Whereas its knockdown caused apoptosis, its over‐ and super‐expressions caused senescence and increase in malignant properties of cancer cells, respectively, and were closely linked to increase and decrease in p53 activity. Using p53‐compromised cancer cells, we demonstrate that CARF induces growth arrest when wild type p53 is present and in p53‐absence, it promotes carcinogenesis. Biochemical analyses on CARF‐induced molecular signaling revealed that in p53‐null cells, it caused transcriptional repression of p21WAF1 leading to increase in CDK4, CDK6, pRb and E2F1 resulting in continued cell cycle progression. Furthermore, it instigated increase in migration and invasion of cancer cells that was marked by upregulation of MMP2, MMP3, MMP9, uPA, several interleukins and VEGF expression. Consistent with these findings, we found that human clinical samples of epithelial and glial cancers (frequently marked by loss of p53 function) possessed high level of CARF expression showing a relationship with cancer aggressiveness. The data demonstrated that CARF could be considered as a diagnostic marker and a therapeutic target in p53‐compromised malignancies.