Role in cancer Cells containing oncogenic mutations in-vivo often responded by activating the<unk> A/ARF/INK4B locus that encodes the<unk>  tumor suppressor proteins. The unusual genomic arrangement of the<unk> a/ARF/INK4b locus functions as a weakness in 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<unk> a/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<unk> a/ARF/INK4b locus to prevent cancer. The response of the<unk> a/ARF/INK4b locus efficiently prevents cancers that could occur to the constant oncogenic mutations that occur in long-lived mammals. When the<unk> a/ARF/INK4b locus was overexpressed, the mice demonstrated a 3-fold reduction in the incidence of spontaneous cancers. This evidence further indicated that the<unk> a/ARF/INK4b locus in mice plays a role in tumor suppression. Role in aging The<unk>  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<unk> a/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<unk> a/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.
INK4
ERCC2
WRAP53
FCER1
BRCA1
P73
Mad2
CoWIN