p27 is regulated independently of Skp2 in the absence of Cdk2

Abstract

Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdks. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27Kip1, which is able to inhibit Cdk2 and Cdk1. Knockdown of Cdk2 abrogated proliferation of Skp2−/− mouse embryonic fibroblasts, encouraging us to generate Cdk2−/−Skp2−/− double knockout mice. Cdk2−/−Skp2−/− double knockout mice are viable and display similar phenotypes as Cdk2−/− and Skp2−/− mice. Unexpectedly, fibroblasts generated from Cdk2−/−Skp2−/− double knockout mice proliferated at normal rates. The increased stability of p27 observed in Skp2−/− MEFs was not observed in Cdk2−/−Skp2−/− double knockout fibroblasts indicating that in the absence of Cdk2, p27 is regulated by Skp2-independent mechanisms. Ablation of other ubiquitin ligases for p27 such as KPC1, DDB1, and Pirh2 did not restore stability of p27 in Cdk2−/−Skp2−/− MEFs. Our findings point towards novel and alternate pathways for p27 regulation.

Nuclear expression of Y‐box binding protein‐1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models

“…However, we found the inhibition of G1/S phase transition concomitant with the decreased SKP2 and CDK2 protein expressions and increased p27 protein in PDAC cells with YB‐1 knockdown. CDK2 may not be a dominant factor for cell cycle progression, because CDK2 knockdown did not increase the cell cycle arrest, which might be explained by compensation through other CDK activities . To the contrary, SKP2 may be responsible for the YB‐1‐mediated G1/S phase transition in PDAC cells, because SKP2 is known to degrade p27 protein and SKP2 siRNA treatment led to the increases in G0/G1 arrest and p27 protein.…”

“…CDK2 may not be a dominant factor for cell cycle progression, because CDK2 knockdown did not increase the cell cycle arrest, which might be explained by compensation through other CDK activities. 38,39 To the contrary, SKP2 may be responsible for the YB-1-mediated G1/S phase transition in PDAC cells, because SKP2 is known to degrade p27 protein 40 and SKP2 siRNA treatment led to the increases in G0/ G1 arrest and p27 protein. The increase in p27 protein seems to be a secondary event by YB-1 activation, because YB-1 knockdown did not affect p27 mRNA expression.…”

Unfolded‐protein response‐associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract

“…We then asked whether induction of the UPR affected the levels of E3 ligases known to be involved in p27 degradation (44)(45)(46)(47)(48)(49)(50). We found that the level of Skp2, the substrate recognition subunit of the E3 that is usually associated with p27 degradation, SCF skp2 (27,39), was significantly reduced upon treatment with TM, whereas the levels of DDB1, KPC1, and Pirh1, other E3s known to target p27 for proteasomal degradation, were not affected (Fig.…”

The importance of ubiquitin E3 ligases, SCF and APC/C, in human cancers

“…The type D cyclines activate Cdk4 and Cdk6 in order to regulate the events in the G1 phase [ 1 ]. Type E and A cyclines activate Cdk2 and Cdk1 with effects on the events of the S phase [ 1 , 4 ]. Type A and B cyclines activate Cdk1 with a direct and regulatory action of the events in the mitosis [ 5 ].…”

“…Type A and B cyclines activate Cdk1 with a direct and regulatory action of the events in the mitosis [ 5 ]. The cyclineE-Cdk2 is activated in the late G1 phase, so as to promote the entry into the S phase and thereafter the DNA replication [ 1 , 4 ]. CyclinA-Cdk2 and cyclinA-Cdk1 are involved in the progression of the S phase and the G2/M transition, while cyclinB-Cdk1 is activated in order to promote the entry into the mitosis [ 1 ].…”