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The p53 tumor suppressor targets a novel regulator of G protein signaling
L Buckbinder1, S Velasco-Miguel, Y Chen
1Department of Molecular Genetics, Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543, USA.
Abstract:
Heterotrimeric G proteins transduce multiple growth-factor-receptor-initiated and intracellular signals that may lead to activation of the mitogen-activated or stress-activated protein kinases. Herein we report on the identification of a novel p53 target gene (A28-RGS14) that is induced in response to genotoxic stress and encodes a novel member of a family of regulators of G protein signaling (RGS) proteins with proposed GTPase-activating protein activity. Overexpression of A28-RGS14p protein inhibits both Gi- and Gq-coupled growth-factor-receptor-mediated activation of the mitogen-activated protein kinase signaling pathway in mammalian cells. Thus, through the induction of A28-RGS14, p53 may regulate cellular sensitivity to growth and/or survival factors acting through G protein-coupled receptor pathways.
Insights
Researchers identified a new p53 target gene, A28-RGS14, activated by genotoxic stress. This gene regulates G protein signaling, potentially controlling cell sensitivity to growth factors via G protein-coupled receptors.
Area of Science:
- Molecular biology
- Cell signaling
- Cancer research
Background:
- Heterotrimeric G proteins are key signal transducers for growth factors and intracellular signals.
- These pathways can activate mitogen-activated or stress-activated protein kinases.
Purpose of the Study:
- To identify novel p53 target genes involved in cellular stress response.
- To investigate the role of A28-RGS14 in G protein signaling and cellular sensitivity to growth factors.
Main Methods:
- Identification of a novel p53 target gene (A28-RGS14) induced by genotoxic stress.
- Characterization of A28-RGS14 as a regulator of G protein signaling (RGS) protein.
- Overexpression studies in mammalian cells to assess effects on mitogen-activated protein kinase (MAPK) signaling.
Main Results:
- A28-RGS14 encodes a novel RGS protein with proposed GTPase-activating protein activity.
- Overexpression of A28-RGS14p inhibits both Gi- and Gq-coupled receptor-mediated MAPK activation.
- p53-induced A28-RGS14 may modulate cellular responses to growth and survival factors.
Conclusions:
- A28-RGS14 is a novel p53 target gene induced by genotoxic stress.
- A28-RGS14 negatively regulates G protein-coupled receptor signaling pathways.
- p53-mediated induction of A28-RGS14 offers a mechanism to control cellular sensitivity to growth factors.