The p21(Cip1) protein, a cyclin inhibitor, regulates the levels and the intracellular localization of CDC25A in mice regenerating livers.
Liver cells from p21(Cip1-/-) mice subjected to partial hepatectomy (PH) progress into DNA synthesis faster than those from wild-type mice. These cells also show a premature induction of cyclin E/cyclin-dependent kinase (CDK) 2 activity. We studied the mechanisms whereby cells lacking p21(Cip1) showed a premature induction of this activity. Whereas the levels of CDK2, cyclin E, and p27(Kip1) were similar in both wild-type and p21(Cip1-/-) mice, those of the activator CDC25A were much higher in p21(Cip1-/-) quiescent and regenerating livers than in wild-type animals. Moreover, p21(Cip1-/-) cells also showed a premature translocation of CDC25A from cytoplasm into the nucleus. The ectopic expression of p21(Cip1) into mice embryo fibroblasts from p21(Cip1-/-) mice decreased the levels of CDC25A and delayed its nuclear translocation. The levels of CDC25A messenger RNA in p21(Cip1-/-) cells were higher than in wild-type cells, suggesting that this increase might be responsible, at least in part, for the high levels of CDC25A protein in these cells. Thus, the results reported here indicate that p21(Cip1) regulates the levels and the intracellular localization of CDC25A. We also found a good correlation between CDC25A nuclear translocation and cyclin E/CDK2 activation. In conclusion, premature translocation of CDC25A to the nucleus might be involved in the advanced induction of cyclin E/CDK2 activity and DNA replication in cells from animals lacking p21(Cip1).
Jaime
Maribel
M
Department of Cell Biology and Pathology, Faculty of Medicine, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Pujol
Maria Jessús
MJ
Serratosa
Joan
J
Pantoja
Cristina
C
Canela
Núria
N
Casanovas
Oriol
O
Serrano
Manuel
M
Agell
Neus
N
Bachs
Oriol
O
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006498:Hepatectomy; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020687:cdc25 Phosphatases / Q000032:analysis / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases