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JNCI Journal of the National Cancer Institute 2001 93(6):415-417; doi:10.1093/jnci/93.6.415
© 2001 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 93, No. 6, 415-417, March 21, 2001
© 2001 Oxford University Press

EDITORIAL

Searching for Selective Cyclin-Dependent Kinase Inhibitors to Target the Retinoblastoma/p16 Cancer Gene Pathway

Akihito Kubo, Frederic J. Kaye

Affiliations of authors: Medicine Branch, Center for Cancer Research, National Cancer Institute, and National Naval Medical Center, Bethesda, MD.

Correspondence to: Frederic J. Kaye, M.D., National Naval Medical Center, Bldg. 8, Rm. 5101, Bethesda, MD 20889 (e-mail: fkaye@helix.nih.gov).

The retinoblastoma protein (pRb)/cyclin/cyclin-dependent kinase (Cdk)/p16 tumor-suppressor pathway participates in the regulation of cellular proliferation and undergoes mutational or epigenetic inactivation in essentially 100% of selected human malignancies, including lung cancer (1,2). Since this pathway is frequently altered by inactivation of either the RB gene or the upstream Cdk4/6-inhibitor gene, Cdkn2a/p16ink4a, it is commonly referred to as the RB/p16 tumor-suppressor pathway. Within this tumor-suppressor pathway, the loss of p16 function results in constitutive Cdk4/6 activation that confers aberrant pRb hyperphosphorylation. pRb hyperphosphorylation, in turn, locks the protein in an "inactive" conformation that disrupts the function of downstream cellular-binding partners, such as members of the E2F family of transcription factors. Surprisingly, the deregulation of E2F by aberrant Cdk activation appears to be similar to the deregulation of E2F observed in tumor cells that lack pRb protein but retain . . . [Full Text of this Article]

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