In most cell lines, p27KlP1 expression is primarily under posttranslational control, as mRNA levels typically remain constant while protein levels decrease throughout G, phase due to an increase in the rate of ubiquitin-targeted proteolytic breakdown. However, during terminal differentiation of trophoblasts, p27Kipl mRNA expression was up-regulated (Fig. 6b) comparable to the up-regulation described in cultured embryonic stem cells induced to form embryoid bodies. The increased expression of p27Kipl protein in cultured trophoblasts may reflect increases in mRNA (Fig. 6b) and/or posttranslational mechanisms. Recent evidence suggests that p27KlP1 protein may be a substrate for cyclin E/Cdk2 kinase activity and that the resulting phosphorylation may increase degradation of p27Kipl protein. Thus, increased levels of p27K,pl protein detected in differentiating trophoblasts may, in part, be a consequence of decreased cyclin E/Cdk2 catalytic activity. buy diabetes drugs
D-type cyclins are thought to represent primary sensors of mitogenic stimuli that govern cell cycle entry/exit in numerous cell types. The loss of D-type cyclins and their associated functions is required for differentiation in many cell types, such as myoblasts and myeloid cells. Pluripotent embryonic stem cells demonstrate an increase in cyclin D protein levels during differentiation; however, the cyclin Dl/Cdk4 complexes formed are inactive due to inhibition by pl6Ink4. Cultured trophoblasts do not express cyclin D1 but did express cyclin D2 and D3 protein, levels of which decline upon differentiation (Fig. 3).