p73 is regulated by phosphorylation at the G2/M transition.
p73 is a p53 paralog that encodes proapoptotic (transactivation-competent (TA)) and antiapoptotic (dominant negative) isoforms. TAp73 transcription factors mediate cell cycle arrest and/or apoptosis in response to DNA damage and are involved in developmental processes in the central nervous system and the immune system. p73 proteins may also play a role in the regulation of cell growth. Indeed, p73 expression is itself modulated during the cell cycle and TAp73 proteins accumulate in S phase cells. In addition, the function of p73 proteins is also regulated by post-translational modifications and protein-protein interactions in different cellular and pathophysiological contexts. Here we show that p73 is a physiological target of the p34cdc2-cyclin B mitotic kinase complex in vivo. Both p73beta and p73alpha isoforms are hyperphosphorylated in normal mitotic cells and during mitotic arrest induced by microtubule-targeting drugs. p34cdc2-cyclin B phosphorylates and associates with p73 in vivo, which results in a decreased ability of p73 to both bind DNA and activate transcription in mitotic cells. Indeed, p73 is excluded from condensed chromosomes in meta- and anaphase, redistributes throughout the mitotic cytoplasm, and unlike p53, shows no association with centrosomes. Together these results indicate that M phase-specific phosphorylation of p73 by p34cdc2-cyclin B is associated with negative regulation of its transcriptional activating function.
Fulco
Marcella
M
Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome "La Sapienza," 00161 Rome, Italy.
Costanzo
Antonio
A
Merlo
Paola
P
Mangiacasale
Rosamaria
R
Strano
Sabrina
S
Blandino
Giovanni
G
Balsano
Clara
C
Lavia
Patrizia
P
Levrero
Massimo
M
D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D016195:G2 Phase; D016147:Genes, Tumor Suppressor; D006801:Humans; D008938:Mitosis; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D019926:Cyclin B; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases