Gene Probes pp 43-59

Part of the Methods in Molecular Biology book series (MIMB, volume 179)

Evaluation of Alterations in the Tumor Suppressor Genes INK4A and INK4B in Human Bladder Tumors

  • Irene Orlow
  • Carlos Cordon-Cardo


The progression through the cell cycle is monitored by positive and negative regulators. One family of negative regulators has been reported to act as cyclin-dependent kinase inhibitors (CKI) (1, 2, 3); and these, in turn, have been subdivided into two groups on the basis of sequence homology. The first CKI family includes p21Cip1 (4, 5, 6), p27Kip1 (7, 8, 9), and p57 Kip2 (10,11). The other CKI subgroup includes four members: p16INK4A/MTS1/CDKN2A (12,13), p15INK4B/MTS2/CDKN2B (14), p18INK4C (15), and p19INK4D (16). The INK4A and INK4B genes map to the short arm of chromosome 9 (9p21), where they are found in tandem spanning a region of approx 80 kilobases (kb) (Fig. 1). The INK4A and the INK4B genes encode for the p16 and the p15 proteins, respectively (12, 13, 14). These protein products form binary complexes exclusively with Cdk4 and Cdk6, inhibiting their function and, by doing so, inhibiting pRB phosphorylation during G1. Additional complexity results from the presence of a second INK4A product, termed p19ARF or p14ARF in humans (ARF is the acronym for alternative reading frame) (17, 18, 19, 20) (Fig. 1). The p19ARF blocks the mdm2-induced p53 degradation and transactivational silencing (21,22). The INK4A is altered in many cell lines and primary tumors (23, 24, 25, 26). Furthermore, germ line mutations of the INK4A gene are found on patients with familial melanoma and pancreatic adenocarcinoma (27, 28); and targeted deletion of the INK4A in murine models is associated with the development of spontaneous tumors (29,30).
Fig. 1.

Genomic organization of the INK4A and INK4B gene locus.


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Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Irene Orlow
    • 1
  • Carlos Cordon-Cardo
    • 2
  1. 1.Department of Epidemiology and BiostatisticsMemorial Sloan-Kettering Cancer Center
  2. 2.Department of PathologyMemorial Sloan-Kettering Cancer CenterNew York

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