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Human chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15 INK4B , p14 ARF  and p16 INK4A ), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15 INK4B  is markedly stronger than p16 INK4A  in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic  HRas  and lacking p15 INK4B , but not those expressing  HRas  and lacking p16 INK4A , develop early-onset bladder tumors. The potency of CDKN2B/p15 INK4B  in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15 INK4B  also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15 INK4B  on cell proliferation, and unveil mechanisms whereby p15 INK4B  aberrations may underpin cancer and non-cancer conditions.

Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis