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

Author

Listed:
  • Yong Xia

    (New York University School of Medicine)

  • Yan Liu

    (New York University School of Medicine)

  • Chao Yang

    (New York University)

  • Diane M. Simeone

    (New York University School of Medicine
    New York University School of Medicine)

  • Tung-Tien Sun

    (New York University School of Medicine)

  • David J. DeGraff

    (The Pennsylvania State University College of Medicine)

  • Moon-shong Tang

    (New York University School of Medicine)

  • Yingkai Zhang

    (New York University)

  • Xue-Ru Wu

    (New York University School of Medicine
    New York University School of Medicine
    Veterans Affairs New York Harbor Healthcare System)

Abstract

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 (p15INK4B, p14ARF and p16INK4A), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15INK4B is markedly stronger than p16INK4A in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic HRas and lacking p15INK4B, but not those expressing HRas and lacking p16INK4A, develop early-onset bladder tumors. The potency of CDKN2B/p15INK4B in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15INK4B also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15INK4B on cell proliferation, and unveil mechanisms whereby p15INK4B aberrations may underpin cancer and non-cancer conditions.

Suggested Citation

  • Yong Xia & Yan Liu & Chao Yang & Diane M. Simeone & Tung-Tien Sun & David J. DeGraff & Moon-shong Tang & Yingkai Zhang & Xue-Ru Wu, 2021. "Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22327-5
    DOI: 10.1038/s41467-021-22327-5
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