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

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 –3 ); and these, in turn, have been subdivided into two groups on the basis of sequence homology. The first CKI family includes p21 ^Cip1 (4 –6 ), p27 ^Kip1 (7 –9 ), and p57 Kip2 (10 ,11 ). The other CKI subgroup includes four members: p16 ^{INK4A/MTS1/CDKN2A} (12 ,13 ), p15 ^{INK4B/MTS2/CDKN2B} (14 ), p18 ^INK4C (15 ), and p19 ^INK4D (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 –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 p19 ^ARF or p14 ^ARF in humans (ARF is the acronym for alternative reading frame) (17 –20 ) (Fig. 1 ). The p19 ^ARF blocks the mdm2 -induced p53 degradation and transactivational silencing (21 ,22 ). The INK4A is altered in many cell lines and primary tumors (23 –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 ).

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