CARF is a multi-module regulator of cell proliferation and a molecular bridge between cellular senescence and carcinogenesis

Renu Wadhwa; Rajkumar Singh Kalra; Sunil C Kaul

doi:10.1016/j.mad.2017.07.008

CARF is a multi-module regulator of cell proliferation and a molecular bridge between cellular senescence and carcinogenesis

Mech Ageing Dev. 2017 Sep:166:64-68. doi: 10.1016/j.mad.2017.07.008. Epub 2017 Jul 25.

Authors

Renu Wadhwa¹, Rajkumar Singh Kalra¹, Sunil C Kaul²

Affiliations

¹ DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science and Technology (AIST), Central 5-41, 1-1-1 Higashi, Tsukuba, Ibaraki, 305 8565 Japan.
² DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science and Technology (AIST), Central 5-41, 1-1-1 Higashi, Tsukuba, Ibaraki, 305 8565 Japan. Electronic address: s-kaul@aist.go.jp.

PMID: 28754531
DOI: 10.1016/j.mad.2017.07.008

Abstract

CARF (Collaborator of ARF) was first identified as an ARF (Alternative Reading Frame, p14ARF)-interacting protein in a yeast two-hybrid interactive screening. Subsequently, it was shown to stabilize the p53-tumor suppressor protein in an ARF-dependent or -independent manner. It acts as a transcriptional repressor of HDM2 that exerts a negative feedback on p53 by its proteasomal-mediated degradation. CARF-driven control over p53-HDM2-p21^WAF1 axis was shown to regulate cell proliferative fates. Cells with CARF-overexpression (CARF-OE) and superexpression (CARF-SE) showed growth arrest and pro-proliferative phenotypes, respectively. On the other hand, apoptosis was triggered in CARF-compromised cells. In the present review, we provide a comprehensive current understanding into the molecular mechanisms of CARF functions in regulation of DNA damage response, cell cycle checkpoints, cell survival and death signaling pathways. We discuss how thresh-hold of CARF level determines fate of cells to senescence and malignant transformation.

Keywords: CARF; Malignant transformation; Overexpression; Senescence; Superexpression.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Cell Cycle Checkpoints*
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Cellular Senescence*
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
DNA Damage*
Humans
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Tumor Suppressor Protein p14ARF / genetics
Tumor Suppressor Protein p14ARF / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Apoptosis Regulatory Proteins
CDKN1A protein, human
CDKN2AIP protein, human
Cyclin-Dependent Kinase Inhibitor p21
RNA-Binding Proteins
TP53 protein, human
Tumor Suppressor Protein p14ARF
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2