Molecular bridging of aging and cancer: A CARF link.

Collaborator of ARF (CARF) was first cloned as an ARF partner in yeast two-hybrid screens. It enhances ARF-dependent and -independent p53 functions, which are central to the control of cell growth and tumor suppression in human cells. CARF interacts with ARF, p53, and MDM2 proteins, and in turn gets regulated by MDM2-mediated degradation, suggesting a self-regulatory loop. CARF is upregulated during replicative, oncogenic, and stress-induced senescence. Overexpression of CARF induced premature senescence in normal human fibroblasts that was mediated by upregulation of p53-p21(CIP1/WAF1) and p16(INK4a)- pRB pathways. Knockdown of CARF resulted in mitotic arrest leading to excessive chromosomal condensation, aneuploidy, and apoptosis, suggesting that CARF is essential for cell survival. Most recently, we have found that CARF causes bidirectional regulation of p53 and pRB pathways, either arresting or promoting growth, and thus, it could be a potential threshold link between aging and cancer.