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Updated: May 18, 2026
14:57
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Putting the brakes on p53-driven apoptosis.
Katja Höpker1, Henning Hagmann, Safiya Khurshid
1Department II of Internal Medicine and Center for Molecular Medicine Cologne, Cologne, Germany.
Cell Cycle (Georgetown, Tex.)
|September 18, 2012
Summary
The p38/MK2/AATF pathway controls whether cells undergo apoptosis or senescence after DNA damage. Inhibiting this pathway enhances chemotherapy effectiveness in tumor cells.
Area of Science:
- Cellular signaling pathways
- DNA damage response
- Cancer biology
Background:
- Genotoxic stress triggers complex signaling networks for DNA repair or apoptosis.
- The tumor suppressor p53 is central to the DNA damage response, mediating target gene expression.
- The precise molecular mechanisms dictating p53-dependent apoptosis versus senescence remain unclear.
Purpose of the Study:
- To elucidate the role of the transcriptional regulator AATF in determining the cellular outcome of p53 signaling.
- To identify novel signaling molecules that regulate the choice between p53-driven apoptosis and senescence.
- To investigate the p38/MK2/AATF pathway as a potential therapeutic target in cancer.
Main Methods:
- Investigated the phosphorylation and localization of AATF upon genotoxic stress.
- Examined the interaction of AATF with MRLC3 and its effect on nuclear translocation.
- Analyzed the binding of AATF to promoters of pro-apoptotic genes (PUMA, BAX, BAK).
- Assessed the impact of AATF depletion on tumor cell response to chemotherapeutics in vitro and in vivo.
- Correlated AATF copy number gains with prognosis in neuroblastoma.
Main Results:
- Genotoxic stress induces p38MAPK/MK2-mediated phosphorylation of cytoplasmic AATF.
- Phosphorylation disrupts AATF:MRLC3 complexes, leading to AATF nuclear localization.
- Nuclear AATF represses the expression of pro-apoptotic genes PUMA, BAX, and BAK.
- AATF depletion enhances tumor cell sensitivity to DNA-damaging agents.
- AATF copy number gains in neuroblastoma correlate with poor prognosis.
Conclusions:
- The p38/MK2/AATF signaling pathway acts as a critical repressor of p53-driven apoptosis in tumor cells.
- AATF's nuclear localization, regulated by p38/MK2, inhibits apoptosis.
- This pathway represents a novel target for therapies aimed at sensitizing tumors to chemotherapy.
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