The Regulation and Function of Cyclin Dependent Kinase 11 (CDK11): Analysis of the Cdc2L1 PPromoter and Elucidation of CDK11p58 Function During Mitosis

摘要

Cancer is a disease that is characterized by genetic mutations that occur leading to an increased propensity for abnormal cellular growth. Chromosome 1p36.3 is lost or aberrant in several tumor types, including neuroblastoma and melanoma. In order to understand the functional significance of chromosome 1p36.3 loss in tumors, our research has been focused on elucidating the function of cyclin dependent kinase 11 (CDK11), a gene that is located within this chromosomal region. CDK11 is a serine/threonine kinase and is a member of the p34cdc2-related family of kinases. CDK11 has multiple isoforms that are involved RNA processing, apoptosis and the cell cycle.CDK11 proteins are encoded by two different genes (Cdc2L1 and Cdc2L2), which are highly homologous to each other and are evolutionarily conserved. Our studies originated from investigating the regulation of the expression of CDK11 genes by isolating and characterizing the Cdc2L1 promoter region. We identified the basal promoter region and found that Cdc2L1 is regulated by transcription factors Ets-1, Skn-1 and E2F-1. Conversely, Cdc2L2 was shown to be regulated by TCF11/Nrf2, Ets-1 and CREB, displaying differential regulation of the two different CDK11 genes.CDK11p58 is generated during the G2/M phase of the cell cycle because of an internal ribosome entry site found within the full-length CDK11 transcript. The generation of CDK11p58 during the cell cycle had previously been shown to be a regulatory event; however the actual function of CDK11p58 remained unknown. Our research focused on determining potential interaction partners of CDK11p58 and elucidating the role of these interactions in the regulation of the cell cycle. Utilizing proteomic technology, we were able to find multiple potential interacting proteins with CDK11p58, including a RNA-dependent RNA helicase protein, DDX15. DDX15 is phosphorylated by CDK11p58 and both proteins are directly involved in cell cycle regulation. Additionally, CDK11p58 was found to associate with several cytoskeletal proteins, alpha- and beta-tubulin, lamin A, and vimentin, and heat shock proteins, Hsp70 and Hsp90. These investigations are only preliminary but provide a novel insight into the possible function of CDK11p58 during mitosis.