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PUMA, a potent killer with or without p53

Oncogene volume 27, pages S71–S83 (2008)Cite this article

Abstract

PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a critical mediator of p53-dependent and -independent apoptosis induced by a wide variety of stimuli, including genotoxic stress, deregulated oncogene expression, toxins, altered redox status, growth factor/cytokine withdrawal and infection. It serves as a proximal signaling molecule whose expression is regulated by transcription factors in response to these stimuli. PUMA transduces death signals primarily to the mitochondria, where it acts indirectly on the Bcl-2 family members Bax and/or Bak by relieving the inhibition imposed by antiapoptotic members. It directly binds and antagonizes all known antiapoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. PUMA ablation or inhibition leads to apoptosis deficiency underlying increased risks for cancer development and therapeutic resistance. Although elevated PUMA expression elicits profound chemo- and radiosensitization in cancer cells, inhibition of PUMA expression may be useful for curbing excessive cell death associated with tissue injury and degenerative diseases. Therefore, PUMA is a general sensor of cell death stimuli and a promising drug target for cancer therapy and tissue damage.

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Abbreviations

AIF:

apoptosis-inducing factor

BH3:

Bcl-2 homology 3

CDK:

cyclin-dependent kinase

CHOP:

C/EBP homologous protein

ChIP:

chromatin immunoprecipitation

Env:

envelope

ER:

endoplasmic reticulum

FoxO3a:

forkhead box O3A

5-FU:

5-fluorouracil

MEF:

mouse embryonic fibroblast

MEK:

mitogen-activated protein/extracellular signal-regulated kinase kinase

6-OHDA:

6-hydroxydopamine

PI3K:

phosphoinositide-3 kinase

PUMA:

p53 upregualted modulator of apoptosis

ROS:

reactive oxygen species

shRNA:

short-hairpin RNA

siRNA:

small-interfering RNA

UV:

ultraviolet

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Acknowledgements

We thank Dr Daniel E Johnson, Dr Crissy P Dudgeon and Mr Joshua Jamison for helpful discussion and critical reading. Work in authors’ laboratories was supported by the NIH grants CA106348, CA121105, the American Cancer Society grant RSG-07-156-01-CNE, the American Lung Association (LZ), the NIH grant CA129829, P50CA097190 (Head and Neck Cancer SPORE Career Development Award), U19-A1068021 (University of Pittsburgh Center for Medical Countermeasures Against Radiation Developmental Research Program) and those from the Hillman Foundation, Alliance for Cancer Gene Therapy (ACGT) and Flight Attendant Medical Research Institute (FAMRI) (JY).

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  1. Department of Pathology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J Yu

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    L Zhang

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Yu, J., Zhang, L. PUMA, a potent killer with or without p53. Oncogene 27 (Suppl 1), S71–S83 (2008). https://doi.org/10.1038/onc.2009.45

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