In contrast, the Ink4 family of cdk inhibitors bind only cdk4 and cdk6, making them specific inhibitors of G1 phase.
Even in this basic scheme it is clear that regulation of the cell cycle is complex and occurs at many levels. Not only are many different types of molecules involved, but many are families of molecules that are expressed in overlapping as well as tissue-specific patterns. In the ovary, cy-clin D2 is highly expressed specifically in granulosa cells, as is cdk4, while cyclin D1 and cyclin D3 are barely detectable and mice lacking cyclin D1 exhibit normal ovarian function. In contrast, cyclin D1 and cyclin D3 are expressed in an overlapping pattern, with both expressed at the highest levels in theca cells. Both p27 and a related family member, p21Cip1, are highly expressed in the corpus luteum with only slightly different patterns of induction.
However, they appear to play unique roles in this tissue, since mice lacking p27 exhibit an altered ovarian phenotype while mice lacking p21 do not. Rb is also a member of a family of molecules (including p107 and p130), and there are five mammalian isoforms of E2F. Mice lacking p107, p130, or E2F-1 are fertile; thus there may exist overlapping expression and functional redundancy within members of these families in granulosa cells. Precedence for this comes from the observation that phosphatase cdc25, which activates the cyclin B-cdc2 complex, is also expressed as three isoforms that are differentially expressed within the ovary. ventolin inhaler
Another layer of complexity is added to this scenario when one considers the fact that hormonal control of expression and activity of cell cycle regulators not only is achieved by different hormones, but also depends on the dose of hormone. Our studies have shown that cAMP and protein kinase A play a role in accelerating granulosa cell proliferation as well as in terminating follicle growth and initiating terminal differentiation. Specifically, the low levels of cAMP generated in response to FSH induce high levels of cyclin D2 and also increase cyclin E (Fig. 5). In contrast, the LH surge and high levels of cAMP rapidly turn off expression of cyclin D2 followed by cyclin E. Conversely, the LH surge markedly increases levels of p27 as well as p21. High levels of cAMP have been known to terminate cell division in other cell types, and in glial cells this is associated with the induction of p27 expression.