Cyclin D1/PRAD1 as a central target in oncogenesis

The role of the PRAD1 gene in human tumorigenesis was demonstrated by its initial cloning from the breakpoint region on chromosome band 11q13 of the inv(11)(p15q13) in a subset of parathyroid adenomas and also by the demonstration of its likely role as the elusive and long-sought Bcl-1 oncogene in t(11;14)-bearing B cell lymphoma. PRAD1 encodes cyclin D1, a member of a family of G1 cyclins, whose cDNA was also cloned by rescue of a defective budding yeast lacking G1 cyclins and through its inducibility by a cytokine. Furthermore, cyclin D1/ PRAD1 appears to be a "driver" oncogene on the 11q13 amplicon in a number of primary human tumors. Transformation and transgenic mice studies have demonstrated that PRAD1 is indeed an oncogene, whose tumorigenic potential requires cooperativity with other oncogenic "hits." It is now established that cancer cells contain multiple genetic changes. There are two categories of cellular genes in which genetic change contributes to development of neoplasia: oncogenes and tumor suppressor genes. Both positive and negative regulatory forces from oncogenes and tumor suppressor genes appear to converge on cyclin D and its associated CDKs. Interestingly, cyclin D1/PRAD1 has been more directly and widely implicated as a key actor in human cancers than have other cyclins and, for that matter, CDKs. Although the functional explanation for this special role of cyclin D1 in oncogenesis remains incomplete, the evidence that cyclin D1/PRAD1 is indeed a central target in oncogenesis is clearcut. An even larger role in cancer can be postulated by more broadly considering other components of the cell cycle regulatory pathway involving cyclin Dl, such as CDK4, p16, and pRb, all of which have been directly implicated in human cancer. It is hoped that further studies will lead to an understanding of the precise role of cyclin D1/PRAD1 in cell cycle control and oncogenesis and also to the rational design of new therapeutic strategies.