Abstract
We address here the involvement of the homeodomain-interacting protein kinase 2 (HIPK2)/p53 complex on MDM2 regulation following apoptotic DNA damage. Our results provide a plausible transcriptional (p53-dependent) and posttranscriptional (p53-independent) double mechanism by which HIPK2 accomplishes MDM2 downmodulation. First, in wtp53-carrying cells HIPK2-dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level. Secondly, HIPK2 interacts with MDM2 in vitro and in vivo and promotes MDM2 nuclear export and proteasomal degradation, in p53-null cellular context. This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro. In response to DNA damage, depletion of HIPK2 by RNA-interference abolishes MDM2 protein degradation. We propose that HIPK2 contributes to drug-induced modulation of MDM2 activity at transcriptional (through p53Ser46 phosphorylation) and posttranscriptional (through p53-independent subcellular re-localization and proteasomal degradation) levels.
| Original language | English |
|---|---|
| Pages (from-to) | 5473-5480 |
| Number of pages | 8 |
| Journal | FEBS Letters |
| Volume | 579 |
| Issue number | 25 |
| DOIs | |
| Publication status | Published - Oct 24 2005 |
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Keywords
- HIPK2
- MDM2
- Nuclear export
- p53
- Phosphorylation
- Proteasomal degradation
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Molecular Biology
Cite this
HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations. / Di Stefano, Valeria; Mattiussi, Marina; Sacchi, Ada; D'Orazi, Gabriella.
In: FEBS Letters, Vol. 579, No. 25, 24.10.2005, p. 5473-5480.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations
AU - Di Stefano, Valeria
AU - Mattiussi, Marina
AU - Sacchi, Ada
AU - D'Orazi, Gabriella
PY - 2005/10/24
Y1 - 2005/10/24
N2 - We address here the involvement of the homeodomain-interacting protein kinase 2 (HIPK2)/p53 complex on MDM2 regulation following apoptotic DNA damage. Our results provide a plausible transcriptional (p53-dependent) and posttranscriptional (p53-independent) double mechanism by which HIPK2 accomplishes MDM2 downmodulation. First, in wtp53-carrying cells HIPK2-dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level. Secondly, HIPK2 interacts with MDM2 in vitro and in vivo and promotes MDM2 nuclear export and proteasomal degradation, in p53-null cellular context. This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro. In response to DNA damage, depletion of HIPK2 by RNA-interference abolishes MDM2 protein degradation. We propose that HIPK2 contributes to drug-induced modulation of MDM2 activity at transcriptional (through p53Ser46 phosphorylation) and posttranscriptional (through p53-independent subcellular re-localization and proteasomal degradation) levels.
AB - We address here the involvement of the homeodomain-interacting protein kinase 2 (HIPK2)/p53 complex on MDM2 regulation following apoptotic DNA damage. Our results provide a plausible transcriptional (p53-dependent) and posttranscriptional (p53-independent) double mechanism by which HIPK2 accomplishes MDM2 downmodulation. First, in wtp53-carrying cells HIPK2-dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level. Secondly, HIPK2 interacts with MDM2 in vitro and in vivo and promotes MDM2 nuclear export and proteasomal degradation, in p53-null cellular context. This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro. In response to DNA damage, depletion of HIPK2 by RNA-interference abolishes MDM2 protein degradation. We propose that HIPK2 contributes to drug-induced modulation of MDM2 activity at transcriptional (through p53Ser46 phosphorylation) and posttranscriptional (through p53-independent subcellular re-localization and proteasomal degradation) levels.
KW - HIPK2
KW - MDM2
KW - Nuclear export
KW - p53
KW - Phosphorylation
KW - Proteasomal degradation
UR - http://www.scopus.com/inward/record.url?scp=26844462296&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=26844462296&partnerID=8YFLogxK
U2 - 10.1016/j.febslet.2005.09.008
DO - 10.1016/j.febslet.2005.09.008
M3 - Article
C2 - 16212962
AN - SCOPUS:26844462296
VL - 579
SP - 5473
EP - 5480
JO - FEBS Letters
JF - FEBS Letters
SN - 0014-5793
IS - 25
ER -