scholarly journals Cell-Free Degradation of p27kip1, a G1 Cyclin-Dependent Kinase Inhibitor, Is Dependent on CDK2 Activity and the Proteasome

1999 ◽  
Vol 19 (2) ◽  
pp. 1190-1201 ◽  
Author(s):  
Hoang Nguyen ◽  
Diana M. Gitig ◽  
Andrew Koff
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
S Phase ◽  
Cycle Phase ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cdk2 Activity ◽  
A Cell ◽  
Specific Factors ◽  
Specific Degradation

ABSTRACT Entry into S phase is dependent on the coordinated activation of CDK4,6 and CDK2 kinases. Once a cell commits to S phase, there must be a mechanism to ensure the irreversibility of this decision. The activity of these kinases is inhibited by their association with p27. In many cells, p27 plays a major role in the withdrawal from the cell cycle in response to environmental cues. Thus, it is likely that p27 is a target of the machinery required to ensure the irreversibility of S-phase entry. We have been interested in understanding the mechanisms regulating p27 at the G1/S transition. In this report, we define a cell-free degradation system which faithfully recapitulates the cell cycle phase-specific degradation of p27. We show that this reaction is dependent on active CDK2 activity, suggesting that CDK2 activity is directly required for p27 degradation. In addition to CDK2, other S-phase-specific factors are required for p27 degradation. At least some of these factors are ubiquitin and proteasome dependent. We discuss the relationships between CDK2 activity, ubiquitin-dependent, and possibly ubiquitin-independent proteasomal activities in S-phase extracts as related to p27.

scholarly journals MAD1 and p27KIP1 Cooperate To Promote Terminal Differentiation of Granulocytes and To Inhibit Myc Expression and Cyclin E-CDK2 Activity

2002 ◽  
Vol 22 (9) ◽  
pp. 3014-3023 ◽  
Author(s):  
Grant A. McArthur ◽  
Kevin P. Foley ◽  
Matthew L. Fero ◽  
Carl R. Walkley ◽  
Andrew J. Deans ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Cyclin E ◽  
Null Alleles ◽  
Cyclin Dependent Kinase ◽  
Similar Treatment ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cdk2 Activity ◽  
Differentiation Inducer

ABSTRACT To understand how cellular differentiation is coupled to withdrawal from the cell cycle, we have focused on two negative regulators of the cell cycle, the MYC antagonist MAD1 and the cyclin-dependent kinase inhibitor p27KIP1. Generation of Mad1/p27KIP1 double-null mice revealed a number of synthetic effects between the null alleles of Mad1 and p27KIP1, including embryonic lethality, increased proliferation, and impaired differentiation of granulocyte precursors. Furthermore, with granulocyte cell lines derived from the Mad1/p27KIP1 double-null mice, we observed constitutive Myc expression and cyclin E-CDK2 kinase activity as well as impaired differentiation following treatment with an inducer of differentiation. By contrast, similar treatment of granulocytes from Mad1 or p27KIP1 single-null mice resulted in differentiation accompanied by downregulation of both Myc expression and cyclin E-CDK2 kinase activity. In the double-null granulocytic cells, addition of a CDK2 inhibitor in the presence of differentiation inducer was sufficient to restore differentiation and reduce Myc levels. We conclude that Mad1 and p27KIP1 operate, at least in part, by distinct mechanisms to downregulate CDK2 activity and Myc expression in order to promote cell cycle exit during differentiation.

Expression of Cyclin E and the Cyclin-Dependent Kinase Inhibitor p27 in Malignant Lymphomas—Prognostic Implications

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 770-777 ◽  
Author(s):  
Martin Erlanson ◽  
Cajsa Portin ◽  
Barbro Linderholm ◽  
Jack Lindh ◽  
Göran Roos ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Cyclin E ◽  
Prognostic Significance ◽  
S Phase ◽  
Phase Fraction ◽  
Serum Lactate Dehydrogenase ◽  
Cyclin Dependent Kinase ◽  
Malignant Lymphomas ◽  
Cyclin Dependent Kinase Inhibitor

Abstract Cyclin E and the cyclin-dependent kinase inhibitor p27 are two important regulators of the G1-S transition modulating the activity of cyclin-dependent kinases. Aberrations in the cell cycle control are often observed in tumors and might even be mandatory in tumor development. To investigate the importance of cell-cycle defects in malignant lymphomas we have characterized the expression of cyclin E and p27 in 105 newly diagnosed lymphomas using immunohistochemistry. A significant, inverse correlation between p27 and cyclin E expression was observed (rs = −.24, P = .02) and both proteins correlated with the S-phase fraction (rs = −.35, P < .001 andrs = .45, P < .001, respectively). The inverse relationship between p27 expression and proliferation was abrogated in some lymphomas, suggesting that p27 downregulation can represent a genuine aberration. Survival analysis was performed in 105 patients with a median observation time of 86 months. Low p27 and high cyclin E expression were significantly associated with a poor prognosis (P = .0001 and .03, respectively). In a multivariate Cox analysis, p27 expression, stage, serum lactate dehydrogenase level, grade, and age were independent prognostic factors, in contrast to S-phase fraction and cyclin E expression. This is the first report showing that p27 expression in malignant lymphomas has independent prognostic significance, which necessitates future studies regarding its more precise biological role in lymphoid tumorogenesis. © 1998 by The American Society of Hematology.

Expression of Cyclin E and the Cyclin-Dependent Kinase Inhibitor p27 in Malignant Lymphomas—Prognostic Implications

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 770-777 ◽  
Author(s):  
Martin Erlanson ◽  
Cajsa Portin ◽  
Barbro Linderholm ◽  
Jack Lindh ◽  
Göran Roos ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Cyclin E ◽  
Prognostic Significance ◽  
S Phase ◽  
Phase Fraction ◽  
Serum Lactate Dehydrogenase ◽  
Cyclin Dependent Kinase ◽  
Malignant Lymphomas ◽  
Cyclin Dependent Kinase Inhibitor

Cyclin E and the cyclin-dependent kinase inhibitor p27 are two important regulators of the G1-S transition modulating the activity of cyclin-dependent kinases. Aberrations in the cell cycle control are often observed in tumors and might even be mandatory in tumor development. To investigate the importance of cell-cycle defects in malignant lymphomas we have characterized the expression of cyclin E and p27 in 105 newly diagnosed lymphomas using immunohistochemistry. A significant, inverse correlation between p27 and cyclin E expression was observed (rs = −.24, P = .02) and both proteins correlated with the S-phase fraction (rs = −.35, P < .001 andrs = .45, P < .001, respectively). The inverse relationship between p27 expression and proliferation was abrogated in some lymphomas, suggesting that p27 downregulation can represent a genuine aberration. Survival analysis was performed in 105 patients with a median observation time of 86 months. Low p27 and high cyclin E expression were significantly associated with a poor prognosis (P = .0001 and .03, respectively). In a multivariate Cox analysis, p27 expression, stage, serum lactate dehydrogenase level, grade, and age were independent prognostic factors, in contrast to S-phase fraction and cyclin E expression. This is the first report showing that p27 expression in malignant lymphomas has independent prognostic significance, which necessitates future studies regarding its more precise biological role in lymphoid tumorogenesis. © 1998 by The American Society of Hematology.

scholarly journals Cellular Response upon Stress: p57 Contribution to the Final Outcome

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Marianna Nicoletta Rossi ◽  
Fabrizio Antonangeli
Keyword(s):  
Cell Cycle ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
Cellular Stress ◽  
Great Effort ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cycle Arrest ◽  
A Cell ◽  
Cycle Regulation

Progression through the cell cycle is one of the most important decisions during the life of a cell and several kinds of stress are able to influence this choice. p57 is a cyclin-dependent kinase inhibitor belonging to the CIP/KIP family and is a well-known regulator of the cell cycle during embryogenesis and tissue differentiation. p57 loss has been reported in a variety of cancers and great effort has been spent during the past years studying the mechanisms of p57 regulation and the effects of p57 reexpression on tumor growth. Recently, growing amount of evidence points out that p57 has a specific function in cell cycle regulation upon cellular stress that is only partially shared by the other CIP/KIP inhibitors p21 and p27. Furthermore, it is nowadays emerging that p57 plays a role in the induction of apoptosis and senescence after cellular stress independently of its cell cycle related functions. This review focuses on the contribution that p57 holds in regulating cell cycle arrest, apoptosis, and senescence after cellular stress with particular attention to the response of cancer cells.

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