P21waf-1-Chk1 pathway monitors G1 phase microtubule integrity and is crucial for restriction point transition.
Microtubule-disruption (MTD) is often thought to arrest the mammalian cell cycle only during mitosis. However, MTD has also been demonstrated to arrest cells during interphase at a G(1)-phase point we call G(1)MTA. Microtubule integrity is now shown to be required for progression past G(1)MTA and the mammalian restriction-point. Neither p21(waf1) nor p27(kip1) are required for MTD-induced G(1)-arrest. Only p21(waf1) is crucial for normal G(1)MTA passage. The p21(waf1)-Chk1-cdc25C-cdc2-checkpoint-pathway is implicated in monitoring this passage. P21(waf1) deletion deregulates G(1)MTA transition and decreases MTD-G(1) arrest, possibly via Chk1 disregulation. Oncogene-induced overexpression of p21(waf1) produced opposite effects on the Chk1-cdc25C-cdc2 pathway and enhanced MTD-G(1) arrest. G(1)MTA thus represents a novel facet of mammalian G(1)/S checkpoint.
Mantel
Charlie R
CR
Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. cmantel@iupui.edu
Gelfano
Vasily M
VM
Kim
Young-June
YJ
McDaniel
Andrew
A
Lee
Younghee
Y
Boswell
H Scott
HS
Broxmeyer
Hal E
HE
D000818:Animals; D018797:Cell Cycle Proteins / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D017353:Gene Deletion; D006801:Humans; D007399:Interphase; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000502:physiology*; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D020687:cdc25 Phosphatases / Q000032:analysis / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D005047:Etoposide; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C517009:CDC25C protein, human; C517010:Cdc25c protein, mouse; D020687:cdc25 Phosphatases; D015739:Nocodazole