TY - JOUR
T1 - MDM2-Regulated Degradation of HIPK2 Prevents p53Ser46 Phosphorylation and DNA Damage-Induced Apoptosis
AU - Rinaldo, Cinzia
AU - Prodosmo, Andrea
AU - Mancini, Francesca
AU - Iacovelli, Stefano
AU - Sacchi, Ada
AU - Moretti, Fabiola
AU - Soddu, Silvia
PY - 2007/3/9
Y1 - 2007/3/9
N2 - In response to DNA damage, p53 induces either cell-cycle arrest or apoptosis by differential transcription of several target genes and through transcription-independent apoptotic functions. p53 phosphorylation at Ser46 by HIPK2 is one determinant of the outcome because it takes place only upon severe, nonrepairable DNA damage that irreversibly drives cells to apoptosis. Here, we show that p53 represses its proapoptotic activator HIPK2 via MDM2-mediated degradation, whereas a degradation-resistant HIPK2 mutant has increased apoptotic activity. Upon cytostatic, nonsevere DNA damage, inhibition of HIPK2 degradation is sufficient to induce p53Ser46 phosphorylation and apoptosis, converting growth-arresting stimuli to apoptotic ones. These findings establish HIPK2 as an MDM2 target and support a model in which, upon nonsevere DNA damage, p53 represses its own phosphorylation at Ser46 due to HIPK2 degradation, supporting the notion that the cell-cycle-arresting functions of p53 include active inhibition of the apoptotic ones.
AB - In response to DNA damage, p53 induces either cell-cycle arrest or apoptosis by differential transcription of several target genes and through transcription-independent apoptotic functions. p53 phosphorylation at Ser46 by HIPK2 is one determinant of the outcome because it takes place only upon severe, nonrepairable DNA damage that irreversibly drives cells to apoptosis. Here, we show that p53 represses its proapoptotic activator HIPK2 via MDM2-mediated degradation, whereas a degradation-resistant HIPK2 mutant has increased apoptotic activity. Upon cytostatic, nonsevere DNA damage, inhibition of HIPK2 degradation is sufficient to induce p53Ser46 phosphorylation and apoptosis, converting growth-arresting stimuli to apoptotic ones. These findings establish HIPK2 as an MDM2 target and support a model in which, upon nonsevere DNA damage, p53 represses its own phosphorylation at Ser46 due to HIPK2 degradation, supporting the notion that the cell-cycle-arresting functions of p53 include active inhibition of the apoptotic ones.
KW - CELLCYCLE
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=33847365838&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847365838&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2007.02.008
DO - 10.1016/j.molcel.2007.02.008
M3 - Article
C2 - 17349959
AN - SCOPUS:33847365838
VL - 25
SP - 739
EP - 750
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -