Linking Cyclins to Transcriptional Control

Cell cycle activation is coordinated by D-type cyclins which are rate limiting and essential for the progression through the G1 phase of the cell cycle. D-type cyclins bind to and activate the cyclin-dependent kinases Cdk4 and Cdk6, which in turn phosphorylate their downstream target, the retinoblastoma protein Rb. Upon Rb phosphorylation, the E2F transcription factors activate the expression of S-phase genes and thereby induce cell cycle progression. The raise of cyclin D levels in early G1 also serves to titrate Kip/Cip proteins away from cyclinE/Cdk2 complexes, further accelerating cell cycle progression. Therefore, cyclin D plays essential roles in the response to mitogens, transmitting their signal to the Rb/E2F pathway. Surprisingly, cyclin D1-deficient animals are viable and have developmental abnormalities limited to restricted tissues, such as retina, the nervous system and breast epithelium. This observation, combined with several other studies, have raised the possibility that cyclin D1 may have new activities that are unrelated to its function as a cdk regulatory subunit and as regulator of Rb. Effectively, cyclin D has been reported to have transcriptional functions since it interacts with several transcription factors to regulate their activity. Most often, this effect does not rely on the kinase function of Cdk4, indicating that this function is probably independent of cell cycle progression. Further extending its role in gene regulation, cyclin D interacts with histone acetylases such as P/CAF or NcoA/SRC1a but also with components of the transcriptional machinery such as TAF(II)250. Therefore, these studies suggest that the functions of cyclin D might need to be reevaluated. They have established a new cdk-independent role of cyclin D1 as a transcriptional regulator, indicating that cyclin D1 can act via two different mechanisms, as a cdk activator it regulates cell cycle progression and as a transcriptional regulator, it modulates the activity of transcription factors.