DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation

Okamoto, Koji; Kashima, Kenji; Pereg, Yaron; Ishida, Michiko; Yamazaki, Satomi; Nota, Ayumi; Teunisse, Amina F.A.S.; Migliorini, Domenico; Kitabayashi, Issay; Marine, Jean–Christophe; Prives, Carol; Shiloh, Yosef; Jochemsen, Aart G.; Taya, Yoichi

doi:10.1128/mcb.25.21.9608-9620.2005

Cited by 110 publications

(127 citation statements)

References 53 publications

(90 reference statements)

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“…[11][12][13] So, we tested whether the expression of MDMX was regulated in neurons by neurotoxic stresses and whether this regulation was dependent on DNA damage-induced pathway. We first investigated the ability of neurotoxic stresses to induce DNA damage using as a marker the phosphorylation of histone H2AX.…”

Section: Resultsmentioning

confidence: 99%

“…[11][12][13] Therefore, we examined the phosphorylation of MDMX at residue 367 after neurotoxic stresses. Interestingly, the phosphorylation of MDMX at residue 367 was induced by both NCS and GLU (Figure 4d), whereas LK had no significant effect, even after more than 10 h of treatment (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Serine 367 phosphorylation has been described to be essential for degradation of MDMX by MDM2 upon DNA damage. [11][12][13] Therefore, it is likely that MDM2 and S367 phosphorylation contribute to the degradation of MDMX in neurons upon neurotoxic treatment. However, it appears that in neurons the mechanisms leading to MDMX degradation can also be different since we did not see any modification of MDMX phosphorylation after LK treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of MDMX at serine 367 was detected by Western blotting using a phospho-specific antibody. 11 Transfections. Cells were cultured in 12-well dishes and grown for 3 days prior to transfection experiments.…”

Section: Methodsmentioning

confidence: 99%

“…MDMX is phosphorylated at multiple sites after cellular stresses, and that these modifications play a critical role in the stability and function of the protein upon DNA damage. [11][12][13] Finally, given that MDMX has been reported to interact with other apoptosis modulating proteins such as E2F-1, 14 ARF, 15 14-3-3, 11 HAUSP 16 and the p53-related proteins p73, 17 it is likely that complex mechanisms underlie MDMX regulation.…”

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Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

et al. 2007

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MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid b precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

et al. 2007

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Regulation of the Cell Cycle, Cell Cycle Checkpoints, and Cancer

Delia

Buscemi

2007

The Cancer Handbook

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DNA damage response (DDR) pathways are triggered to ensure proper repair of DNA lesions and preserve genome integrity. Key intracellular transducers of the DNA damage are ataxia‐telangiectasia mutated kinase (ATM) and ataxia‐telangiectasia and Rad3‐related kinase (ATR). These nuclear proteins, through dynamic interaction with chromatin‐bound sensory components and phosphorylation at T/SQ residues of a multitude of substrates, including the checkpoint kinases Chk1 and Chk2, activate a network of pathways important for DNA repair, multiple cell cycle–phase arrest, transcription, and apoptosis. Interestingly, the DDR machinery is a key mediator of telomere‐dependent and telomere‐independent forms of cellular senescence, and provides a barrier to aberrant DNA replication induced by oncogenic stimuli. These findings and the constitutive activation of the DDR in human precancerous lesions, underscore the role of the DDR as a tumour suppressor constraining transformation by driving incipient tumour cells into apoptosis or senescence. Since genetic abnormalities of the DDR hypersensitize to genotoxic anticancer agents, this pathway represents a relevant target to increase tumour cell kill and possibly overcome drug resistance. The promising results with a number of chemical inhibitors of ATM, Chk1 and Chk2 are paving the way for new chemoradiation strategies that exploit the DDR machinery.

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