Evidence for a CDK4-dependent checkpoint in a conditional model of cellular senescence

Abstract

Cellular senescence, the stable cell cycle arrest elicited by various forms of stress, is an important facet of tumor suppression. Although much is known about the key players in the implementation of senescence, including the pRb and p53 axes and the cyclin dependent kinase inhibitors p16INK4a and p21CIP1, many details remain unresolved. In studying conditional senescence in human fibroblasts that express a temperature sensitive SV40 large T-antigen (T-Ag), we uncovered an unexpected role for CDK4. At the permissive temperature, where pRb and p53 are functionally compromised by T-Ag, cyclin D-CDK4 complexes are disrupted by the high p16INK4a levels and reduced expression of p21CIP1. In cells arrested at the non-permissive temperature, p21CIP1 promotes reassembly of cyclin D-CDK4 yet pRb is in a hypo-phosphorylated state, consistent with cell cycle arrest. In exploring whether the reassembled cyclin D-CDK4-p21 complexes are functional, we found that shRNA-mediated knockdown or chemical inhibition of CDK4 prevented the increase in cell size associated with the senescent phenotype by allowing the cells to arrest in G1 rather than G2/M. The data point to a role for CDK4 kinase activity in a G2 checkpoint that contributes to senescence.

Regulation of senescence escape by the cdk4–EZH2–AP2M1 pathway in response to chemotherapy

“…In this work, we pursued our experiments on CIS escape, showing that the cdk4 kinase is involved in cell emergence. As previously reported 29 , 30 , we also observed that cyclin D1 was upregulated early during CIS escape. It is not really surprising that the cdk4–E2F pathway is involved in the proliferation of PLD subclones and we can speculate that its classical cell cycle targets are involved in emergence.…”

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

“…P53 can mediate cell response to DNA damage, replicative aging due to telomere shortening, as well as stress-induced premature senescence. Its downstream factor p21 can inhibit CDK2 and CDK4, rendering them unable to phosphorylate pRB [19,20]. The resultant hypo-phosphorylated pRB can bind to E2F and prevent it from binding to target genes, thereby prohibiting cells from entering the S phase.…”

Cinnamomi ramulus exhibits anti-proliferative and anti-migration effects on MH7A rheumatoid arthritis-derived fibroblast-like synoviocytes through induction of apoptosis & cell arrest and suppression of matrix metalloproteinase

“…complex plays a role in G1 phase, and the cell cycle enters G1 phase when CDK4 and CDK6 form active complexes with D-type cyclins. However, a recent study found that CDK4 plays an unexpected role in the G2/M checkpoint [34,35]. In this study, we…”