Genetic Alterations of Cyclins, Cyclin-Dependent Kinases, and Cdk Inhibitors in Human Cancer

This chapter focuses on the genetic alterations of cyclins, cyclin dependent kinases (Cdk), and Cdk inhibitors in human cancer. Contemporary research into the molecular basis of cancer has two central tenets. The first is that cancer arises through alterations in the genetic make-up of the tumor cell. The second is that these changes are manifested in the breakdown of the processes that regulate cell growth and differentiation. In simplistic terms, cancer cells proliferate uncontrollably and fail to differentiate. The large numbers of tumors that show perturbations in the D cyclins themselves, their upstream regulators, or their downstream targets suggest that this pathway is extremely important in human cancer and holds great promise for therapeutic intervention. The conventional view of the cell division cycle is as a series of checkpoints or transitions at which certain criteria must be met before the cell proceeds to the next phase. The cyclin D1 gene, now given the locus designation CCNDI, maps to band q13 on the long arm of chromosome 11. The chapter also discusses the amplification of cyclin D1 in human tumors. When the gene for Cdk4 was located on chromosome 12q13, it was quickly realized that it too lies within a tumor-specific amplicon, which had been previously observed in human sarcomas of various types and in tumors of the central nervous system, particularly gliomas. There has been a great deal of interest in the cyclin-dependent kinase inhibitors that have been identified in mammalian cells. The chapter describes cyclin D1-p16-pRb pathway.