cks proteins
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2019 ◽  
Vol 39 (13) ◽  
Author(s):  
Zdenka Ellederova ◽  
Sonia del Rincon ◽  
Marketa Koncicka ◽  
Andrej Susor ◽  
Michal Kubelka ◽  
...  

ABSTRACT Cell division cycle (Cdc) kinase subunit (CKS) proteins bind cyclin-dependent kinases (CDKs) and play important roles in cell division control and development, though their precise molecular functions are not fully understood. Mammals express two closely related paralogs called CKS1 and CKS2, but only CKS2 is expressed in the germ line, indicating that it is solely responsible for regulating CDK functions in meiosis. Using cks2−/− knockout mice, we show that CKS2 is a crucial regulator of maturation-promoting factor (MPF; CDK1-cyclin A/B) activity in meiosis. cks2−/− oocytes display reduced and delayed MPF activity during meiotic progression, leading to defects in germinal vesicle breakdown (GVBD), anaphase-promoting complex/cyclosome (APC/C) activation, and meiotic spindle assembly. cks2−/− germ cells express significantly reduced levels of the MPF components CDK1 and cyclins A1/B1. Additionally, injection of MPF plus CKS2, but not MPF alone, restored normal GVBD in cks2−/− oocytes, demonstrating that GVBD is driven by a CKS2-dependent function of MPF. Moreover, we generated cks2cks1/cks1 knock-in mice and found that CKS1 can compensate for CKS2 in meiosis in vivo, but homozygous embryos arrested development at the 2- to 5-cell stage. Collectively, our results show that CKS2 is a crucial regulator of MPF functions in meiosis and that its paralog, CKS1, must be excluded from the germ line for proper embryonic development.



2017 ◽  
Vol 37 (20) ◽  
Author(s):  
Ruiling Mu ◽  
John Tat ◽  
Robert Zamudio ◽  
Yaoyang Zhang ◽  
John R. Yates ◽  
...  

ABSTRACT CKS proteins are small (9-kDa) polypeptides that bind to a subset of the cyclin-dependent kinases. The two paralogs expressed in mammals, Cks1 and Cks2, share an overlapping function that is essential for early development. However, both proteins are frequently overexpressed in human malignancy. It has been shown that CKS protein overexpression overrides the replication stress checkpoint, promoting continued origin firing. This finding has led to the proposal that CKS protein-dependent checkpoint override allows premalignant cells to evade oncogene stress barriers, providing a causal link to oncogenesis. Here, we provide mechanistic insight into how overexpression of CKS proteins promotes override of the replication stress checkpoint. We show that CKS proteins greatly enhance the ability of Cdk2 to phosphorylate the key replication initiation protein treslin in vitro. Furthermore, stimulation of treslin phosphorylation does not occur by the canonical adapter mechanism demonstrated for other substrates, as cyclin-dependent kinase (CDK) binding-defective mutants are capable of stimulating treslin phosphorylation. This effect is recapitulated in vivo, where silencing of Cks1 and Cks2 decreases treslin phosphorylation, and overexpression of wild-type or CDK binding-defective Cks2 prevents checkpoint-dependent dephosphorylation of treslin. Finally, we provide evidence that the role of CKS protein-dependent checkpoint override involves recovery from checkpoint-mediated arrest of DNA replication.



2009 ◽  
Vol 9 (1) ◽  
pp. 145-152 ◽  
Author(s):  
Marko Radulovic ◽  
Eleanor Crane ◽  
Mark Crawford ◽  
Jasminka Godovac-Zimmermann ◽  
Veronica P. C. C. Yu


2005 ◽  
Vol 280 (34) ◽  
pp. 30448-30459 ◽  
Author(s):  
Markus A. Seeliger ◽  
Martin Spichty ◽  
Sadie E. Kelly ◽  
Mark Bycroft ◽  
Stefan M. V. Freund ◽  
...  


Cell Cycle ◽  
2003 ◽  
Vol 2 (4) ◽  
pp. 274-275 ◽  
Author(s):  
Peter J. Donovan ◽  
Steven I. Reed


2001 ◽  
Vol 11 (11) ◽  
pp. R431-R435 ◽  
Author(s):  
J.Wade Harper
Keyword(s):  


1998 ◽  
Vol 18 (7) ◽  
pp. 3659-3667 ◽  
Author(s):  
Elizabeth A. Egan ◽  
Mark J. Solomon

ABSTRACT Although Cks proteins were the first identified binding partners of cyclin-dependent protein kinases (cdks), their cell cycle functions have remained unclear. To help elucidate the function of Cks proteins, we examined whether their binding to p34 cdc2 (the mitotic cdk) varies during the cell cycle in Xenopusegg extracts. We observed that binding of human CksHs2 to p34 cdc2 was stimulated by cyclin B. This stimulation was dependent on the activating phosphorylation of p34 cdc2 on Thr-161, which follows cyclin binding and is mediated by the cdk-activating kinase. Neither the inhibitory phosphorylations of p34 cdc2 nor the catalytic activity of p34 cdc2 was required for this stimulation. Stimulated binding of CksHs2 to another cdk, p33 cdk2 , required both cyclin A and activating phosphorylation. Our findings support recent models that suggest that Cks proteins target active forms of p34 cdc2 to substrates.



1996 ◽  
Vol 6 (11) ◽  
pp. 1399-1402 ◽  
Author(s):  
Jonathon Pines
Keyword(s):  


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