INK4

[2] In addition, INK4 proteins play roles in cellular senescence, apoptosis and DNA repair.

[1] Polymorphisms of the p15INK4b/p16INK4a homolog were found to segregate with melanoma susceptibility in Xiphophorus indicating that INK4 proteins have been involved with tumor suppression for over 350 million years.

Furthermore, the older INK4-based system has been further bolstered by the evolution of the recent addition of the ARF-based anti-cancer response.

This allows the hypophosphorylated Rb to repress transcription of S-phase genes causing cell cycle arrest in the G1 phase.

[9] Cells containing oncogenic mutations in-vivo often responded by activating the INK4A/ARF/INK4B locus that encodes the INK4 tumor suppressor proteins.

[1] 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 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.

[10] Initially, it was thought that each INK4 family member was structurally redundant and equally potent.

The diversity in expression pattern indicates that the INK4 gene family may have cell lineage-specific or tissue-specific functions.

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.