Surprisingly, mutations or deletions of the genes encoding CDK inhibitors other than p16INK4A are by far not as frequent in human cancers. The CDKN2B gene encoding p15INK4B is located within 40 kb of CDKN2A (cf. Figure 5.9) and is often deleted together with its neighbor. However, inactivation of the gene may only be crucial in certain leukemias. Inactivation of CDKN1C, in accord with its more circumscribed expression, may be relevant in a tighter range of cancers. Mutations in the genes encoding p21CIP1 and p27KIP1 seem very rare in human cancers, but down-regulation of their expression is highly prevalent in many different cancers. It is often a good indication of tumor progression and a marker for cancers taking a more aggressive clinical course. It is neither well understood, why these genes are so rarely mutated nor which mechanisms exactly lead to down-regulation of their expression during tumor progression. In some cases, loss of p27KIP1 may be caused by over-expression of proteins involved in its degradation at the end of G1 (^6.4).

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