p53 displacement from centrosomes and p53-mediated G1 arrest following transient inhibition of the mitotic spindle.
Growing evidence indicates a central role for p53 in mediating cell cycle arrest in response to mitotic spindle defects so as to prevent rereplication in cells in which the mitotic division has failed. Here we report that a transient inhibition of spindle assembly induced by nocodazole, a tubulin-depolymerizing drug, triggers a stable activation of p53, which can transduce a cell cycle inhibitory signal even when the spindle-damaging agent is removed and the spindle is allowed to reassemble. Cells transiently exposed to nocodazole continue to express high levels of p53 and p21 in the cell cycle that follows the transient exposure to nocodazole and become arrested in G(1), regardless of whether they carry a diploid or polyploid genome after mitotic exit. We also show that p53 normally associates with centrosomes in mitotic cells, whereas nocodazole disrupts this association. Together these results suggest that the induction of spindle damage, albeit transient, interferes with the subcellular localization of p53 at specific mitotic locations, which in turn dictates cell cycle arrest in the offspring of such defective mitoses.
Ciciarello
M
M
Consiglio Nazionale delle Ricerche Centre of Evolutionary Genetics, Department of Genetics and Molecular Biology, University of Rome "La Sapienza," Via degli Apuli 4, Rome 00185, Italy.
Mangiacasale
R
R
Casenghi
M
M
Zaira Limongi
M
M
D'Angelo
M
M
Soddu
S
S
Lavia
P
P
Cundari
E
E
D000705:Anaphase; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D002469:Cell Separation; D018385:Centrosome / Q000378:metabolism*; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D016193:G1 Phase; D006801:Humans; D020014:K562 Cells; D008677:Metaphase; D008856:Microscopy, Fluorescence; D008938:Mitosis; D015739:Nocodazole / Q000494:pharmacology; D011003:Ploidies; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000378:metabolism*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D015739:Nocodazole