our anti-cancer defenses. This is due to the fact that three crucial regulators of the RB and p53 (regulated by ARF) are vulnerable to one single, small deletion. This observation yields two possible opposing conclusions: Either tumor formation does not provide any evolutionary selection pressure because the overlapping INK4a/ARF/INK4b is not selected against or tumorigenesis provides such a strong pressure, that an entire group of genes has been selected for at the INK4a/ARF/INK4b locus to prevent cancer. The response of the INK4a/ARF/INK4b locus efficiently prevents cancers that could occur to the constant oncogenic mutations that occur in long-lived mammals. When the INK4a/ARF/INK4b locus was overexpressed, the mice demonstrated a 3-fold reduction in the incidence of spontaneous cancers. This evidence further indicated that the INK4a/ARF/INK4b locus in mice plays a role in tumor suppression. Role in aging The INK4 family has been implicated in the aging process. The expression of p16INK4a increases with aging in many tissues of rodents and humans. It was also shown that INK4a/ARF deficient animals increase an age-related decline in T-cell responsiveness to CD3 and CD28, which is a hallmark of aging. Furthermore, neural stem cells from Bmi-1- deficient animals demonstrate increased INK4a/ARF expression and impaired regenerative potential. The phenotype; however, can be rescued by p16INK4a deficiency implying that while p16INK4a can potentially be used as a biomarker of physiologic, rather than chronologic age, it is also an effector of aging. The mechanism by which it does this is by limiting the self-renewal capacity of disparate tissues such as lymphoid organs, bone marrow, and the brain. Regulation of INK4 expression Initially, it was thought that each INK4 family member was structurally redundant and equally potent. It was later found; however, that INK4 family members are differentially expressed during mouse development. The diversity in expression pattern indicates that the INK4 gene family may have cell lineage-specific or tissue-specific functions. Evidence has shown that INK4a/ARF expression increase at an early stage of tumorigenesis, but the precise stimuli relevant to cancer that induces the expression of the locus is unknown. Expression of p15INK4b does not correlate with p16INK4a in many normal rodent tissues. Induction and repression of p15INK4b; however, has been noted in response to a few signaling events such as RAS activation, that also induce INK4/ARF expression. RAS activation might lead to increased INK4/ARF expression potentially through ERK-mediated activation of Ets1/2 to induce p16INK4. A few repressors of INK4a/ARF/INK4b expression have been identified as well. T box proteins and the polycomb group have been shown to repress p16INK4a, p15INK4b, and ARF. References Category:Protein families Category:Cell cycle Category:Tumor suppressor genes