Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G ₁ /S transition

Abstract

The G1/S-phase transition is a well-toned switch in the mammalian cell cycle. Cdk2, Cdk4, and the rate-limiting tumor suppressor retinoblastoma protein (Rb) have been studied in separate animal models, but interactions between the kinases and Rb in vivo have yet to be investigated. To further dissect the regulation of the G 1 to S-phase progression, we generated Cdk2 ؊/؊ Cdk4 ؊/؊ Rb ؊/؊ (TKO) mutant mice. TKO mice died at midgestation with major defects in the circulatory systems and displayed combined phenotypes of Rb ؊/؊ and Cdk2 ؊/؊ Cdk4 ؊/؊ mutants. However, TKO mouse embryonic fibroblasts were not only resistant to senescence and became immortal but displayed enhanced S-phase entry and proliferation rates similar to wild type. These effects were more remarkable in hypoxic compared with normoxic conditions. Interestingly, depletion of the pocket proteins by HPV-E7 or p107/p130 shRNA in the absence of Cdk2/Cdk4 elicited a mechanism for the G 1/S regulation with increased levels of p27 Kip1 binding to Cdk1/ cyclin E complexes. Our work indicates that the G 1/S transition can be controlled in different ways depending on the situation, resembling a regulatory network.cell cycle ͉ p27 ͉ retinoblastoma protein ͉ Skp2

Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression In vivo

“…Ink4a expression cooperatively blocks the activation of both cyclin D kinase (CDK4/6) and cyclin E kinase (CDK2), allowing the accumulation of the dephosphorylated form of the retinoblastoma tumor suppressor protein (pRb) and thereby causing permanent cell cycle arrest (7)(8)(9)(10). It has become apparent that cellular senescence can be induced by a variety of potentially oncogenic stimuli, such as telomere shortening, DNA damage, oxidative stress, or oncogene expression (11)(12)(13)(14), suggesting that cellular senescence is likely to act as a tumor suppression mechanism in vivo (15,16).…”

Bafetinib inhibits ishikawa cells growth through modulating p16 expression

“…As we expected, this drug induces p16 expression by unknown mechanism. It could be through activation of Rb, which activates p16 (18,19), or may be through p16 demethylation that results in increasing p16 expression (20). Hence, further work should be performed to determine the exact mechanism by which p16 is up regulated by bafetinib.…”

Regulation of the G1/S Transition in Adult Liver: Expression and Activation of the Cyclin Dependent Kinase Cdk1 in Differentiated Hepatocytes is Controlled by Extracellular Signals and is Crucial for Commitment to DNA Replication

“…In mammalian cells, the involvement of Cdk1 in S phase may have been underestimated mainly because the low levels of active Cdk1 compared to the high levels of Cdk2 during DNA replication suggested that Cdk2 was predominant over Cdk1 at this step of the cell cycle (Bashir and Pagano, 2005). In this emerging picture of the cell cycle regulation, these new data probably did not profoundly affect the roles that were initially attributed to the different Cdk/cyclin complexes but rather introduce the notion of redundancy and flexibility (Li et al, 2009b;Satyanarayana and Kaldis, 2009b (Li et al, 2009a;Malumbres et al, 2004;Satyanarayana and Kaldis, 2009b). These deletions did not affect early embryogenesis demonstrating multiple compensatory mechanisms and overlapping roles of these genes.…”