PPM1D Human
Description
Introduction to PPM1D (Human Protein Phosphatase Magnesium-Dependent 1D)
PPM1D (Protein Phosphatase Magnesium-Dependent 1D), also known as Wip1, is a serine/threonine phosphatase encoded by the PPM1D gene located on chromosome 17q23.3 . It belongs to the PP2C family of phosphatases and acts as a critical regulator of stress response pathways, particularly through its interaction with tumor suppressor p53 and DNA damage response (DDR) mechanisms . PPM1D is frequently dysregulated in cancers and has emerged as a therapeutic target due to its oncogenic properties .
Enzymatic Properties:
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Substrate specificity for phospho-Ser/Thr residues in p53 (e.g., p53-S15), p38 MAPK, and ATM kinase .
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Exhibits hysteretic enzyme behavior, with magnesium concentration-dependent lag phases .
Biological Functions and Regulatory Mechanisms
PPM1D modulates cellular stress responses through:
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p53 Pathway Suppression: Dephosphorylates p53-S15, reduces p53-K382 acetylation, and destabilizes MDM2, attenuating apoptosis and senescence .
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DDR Termination: Inactivates ATM kinase and resolves γH2AX foci to terminate DNA damage checkpoints .
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Oncogenic Signaling: Promotes mTORC1 and RAS-driven proliferation while suppressing cGAS/STING-mediated immune activation .
Key Oncogenic Mechanisms:
Functional Consequences:
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Genomic Instability: Truncated PPM1D promotes micronuclei formation and chromosomal rearrangements .
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Therapy Resistance: Confers resistance to ionizing radiation and cytarabine in AML .
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Immune Evasion: Reduces cGAS/STING signaling by suppressing micronuclei-induced interferon responses .
Therapeutic Strategies:
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PPM1D Inhibitors: GSK2830371 sensitizes leukemia cells to chemotherapy and radiation in p53-dependent manner .
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Combination Therapies: Synergistic effects observed with PARP inhibitors in PPM1D-mutant cancers .
Clinical Trials and Outcomes:
| Approach | Model System | Outcome |
|---|---|---|
| Genetic knockout | Mouse HSCs | Reduced self-renewal, increased chemotherapy sensitivity |
| Pharmacological inhibition | AML xenografts | Prolonged survival (p < 0.01) |
Pathogenic Variants:
Germline vs. Somatic Mutations:
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Germline PPM1D mutations predispose to multi-organ cancer risk .
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Somatic mutations drive clonal expansion in aging hematopoietic systems .
Research Gaps and Future Directions
Product Specs
Product Science Overview
PPM1D plays a crucial role in the negative regulation of the p53 tumor suppressor pathway. The expression of PPM1D is induced in a p53-dependent manner in response to various environmental stresses. Once expressed, PPM1D dephosphorylates and inactivates p38 MAP kinase (MAPK/p38), which in turn reduces the phosphorylation of p53. This feedback loop helps to suppress p53-mediated transcription and apoptosis, thereby contributing to growth inhibition and the suppression of stress-induced apoptosis .
The PPM1D gene is located in a chromosomal region that is often amplified in breast cancer. Amplification of this gene has been detected in both breast cancer cell lines and primary breast tumors, suggesting a role in cancer development. Additionally, mutations in PPM1D have been associated with Jansen-De Vries Syndrome, a rare genetic disorder .
Recombinant human PPM1D is widely used in research to study its role in cell cycle regulation, stress response, and cancer development. Understanding the function and regulation of PPM1D can provide insights into potential therapeutic targets for cancer treatment and other diseases associated with cell stress response pathways .
