Cyclin E Ablation in the Mouse

Abstract

E type cyclins (E1 and E2) are believed to drive cell entry into the S phase. It is widely assumed that the two E type cyclins are critically required for proliferation of all cell types. Here, we demonstrate that E type cyclins are largely dispensable for mouse development. However, endoreplication of trophoblast giant cells and megakaryocytes is severely impaired in the absence of cyclin E. Cyclin E-deficient cells proliferate actively under conditions of continuous cell cycling but are unable to reenter the cell cycle from the quiescent G(0) state. Molecular analyses revealed that cells lacking cyclin E fail to normally incorporate MCM proteins into DNA replication origins during G(0)-->S progression. We also found that cyclin E-deficient cells are relatively resistant to oncogenic transformation. These findings define a molecular function for E type cyclins in cell cycle reentry and reveal a differential requirement for cyclin E in normal versus oncogenic proliferation.

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

“…Cdk2 is known to be active in complex with cyclin E at the G 1 -S boundary, and in complex with cyclin A during S-phase progression (Shapiro, 2006). Although it has been described that cdk2 is not an essential gene in the mouse, (Berthet et al, 2003;Geng et al, 2003;Ortega et al, 2003;Tetsu and McCormick, 2003) an overexpression of cdk2 with associated cyclins has been shown in several tumors (Al-Aynati et al, 2004;Olofsson et al, 2004). Furthermore, cdk2 has been recently found to be required for centrosome duplication in mammalian cells (Matsumoto et al, 1999;Matsumoto and Maller, 2004) suggesting that inhibition of cdk2 activity would be an effective anticancer approach.…”

Developmental expression of Cyclin H and Cdk7 in zebrafish: the essential role of Cyclin H during early embryo development

“…Studies have demonstrated normal fetal development following disruption of the D-and E-type cyclins, Cdk4, Cdk6 and Cdk2, suggesting that the individual functions of these genes were not essential for cell cycle progression [27,28]. One possible explanation is that cyclins that promote entry into the S phase in yeast are deleted This cyclin complementation has been demonstrated in mammalian cells [29].…”

Do cells need CDK2 and...Bcr-Abl?

“…44 In the presence of elevated E2F, associated with cancer, inhibition of CDK2 can lead to apoptosis. 45 Given recent findings, 1,[9][10][11][12][13][14][15][16]46 there is no reason to think that CDK2 is universally needed to all normal cells. Likely, certain types of normal cells are CDK2 independent.…”