Deconstructing p53 transcriptional networks in tumor suppression

doi:10.1016/j.tcb.2011.10.006

Trends in Cell Biology

Volume 22, Issue 2, February 2012, Pages 97-106

https://doi.org/10.1016/j.tcb.2011.10.006 Get rights and content

p53 is a pivotal tumor suppressor that induces apoptosis, cell-cycle arrest and senescence in response to stress signals. Although p53 transcriptional activation is important for these responses, the mechanisms underlying tumor suppression have been elusive. To date, no single or compound mouse knockout of specific p53 target genes has recapitulated the dramatic tumor predisposition that characterizes p53-null mice. Recently, however, analysis of knock-in mice expressing p53 transactivation domain mutants has revealed a group of primarily novel direct p53 target genes that may mediate tumor suppression in vivo. We present here an overview of well-known p53 target genes and the tumor phenotypes of the cognate knockout mice, and address the recent identification of new p53 transcriptional targets and how they enhance our understanding of p53 transcriptional networks central for tumor suppression.

Section snippets

p53: complexity at a molecular and network scale

p53 has been studied extensively owing to its paramount importance in tumor suppression. The significance of p53 in tumor suppression in humans is highlighted by its inactivation in over half of all human cancers and by the dramatic cancer predisposition of individuals with Li–Fraumeni syndrome, who inherit a mutant p53 allele. In addition, mice deficient for p53 develop cancer with 100% penetrance 1, 2. Although we have some understanding of the molecular mechanisms by which p53 functions in

Revealing in vivo roles of p53 apoptosis target genes

Mouse models have demonstrated the importance of p53 apoptotic function in tumor suppression (Box 1) [18]. Investigating p53 apoptotic target genes may therefore be important for understanding the molecular mechanisms of p53-mediated tumor suppression. p53 can trigger apoptosis via the intrinsic or extrinsic signaling pathways, which converge at the level of caspase activation but differ in upstream stimuli. The intrinsic apoptotic pathway is regulated by the ratio of pro-apoptotic to

Analysis of p53 TAD mutant knock-in mice

p53 target-gene knockout mice have failed to resolve fully the role of p53 transcriptional activation in tumor suppression. Although analysis of these mice has revealed tumor phenotypes in a very context-dependent manner, it is unclear whether these tumor phenotypes relate to loss of function as direct p53 target genes. Furthermore, the possibility that transactivation-independent functions of p53 are required for tumor suppression cannot be excluded. As mentioned above, p53 has two discrete

Concluding remarks

Deciphering the molecular mechanisms underlying p53 function in tumor suppression is crucial for broadly understanding cancer development. Although p53 is unequivocally involved in eliciting senescence or apoptosis in response to cellular stress signals, the molecular details of p53 action in tumor suppression have remained surprisingly elusive. It has been challenging to map the transcriptional effectors of p53 tumor-suppressor function because of the subtle tumor phenotypes of single or

Acknowledgments

We thank Colleen Brady, Daniela Kenzelmann Brož, Jeanine Frey and Dadi Jiang for critical reading of the manuscript. We apologize to authors whose work could not be cited because of space constraints.

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Trends in Cell Biology

ReviewDeconstructing p53 transcriptional networks in tumor suppression

Section snippets

p53: complexity at a molecular and network scale

Revealing in vivo roles of p53 apoptosis target genes

Analysis of p53 TAD mutant knock-in mice

Concluding remarks

Acknowledgments

Cell

J. Biol. Chem.

Cell

Cancer Cell

J. Biol. Chem.

Biochim. Biophys. Acta

Mol. Cell

Cancer Cell

Cell Stem Cell

Mol. Cell

Cell

Cell

Cell

Mol. Cell

Cell

Mol. Cell

Mutat. Res.

Cell

Curr. Biol.

p53 at a glance

J. Cell Sci.

Cell-cycle checkpoints and cancer

Nature

An oncogene-induced DNA damage model for cancer development

Science

The pathological response to DNA damage does not contribute to p53-mediated tumour suppression

Nature

Tumour biology: policing of oncogene activity by p53

Nature

Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression

PLoS ONE

When mutants gain new powers: news from the mutant p53 field

Nat. Rev. Cancer

Definition of a p53 transactivation function-deficient mutant and characterization of two independent p53 transactivation subdomains

Oncogene

Two tandem and independent sub-activation domains in the amino terminus of p53 require the adaptor complex for activity

Oncogene

The isoforms of the p53 protein

Cold Spring Harb. Perspect. Biol.

Modulation of mammalian life span by the short isoform of p53

Genes Dev.

The p53QS transactivation-deficient mutant shows stress-specific apoptotic activity and induces embryonic lethality

Nat. Genet.

Transcriptional control of human p53-regulated genes

Nat. Rev. Mol. Cell Biol.

Role of p53 serine 46 in p53 target gene regulation

PLoS ONE

Bax involvement in p53-mediated neuronal cell death

J. Neurosci.

Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system

Proc. Natl. Acad. Sci. U.S.A.

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J. Neurosci. Res.

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Proc. Natl. Acad. Sci. U.S.A.

Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo

Oncogene

Bax-deficient mice with lymphoid hyperplasia and male germ cell death

Science

Bax accelerates tumorigenesis in p53-deficient mice

Cancer Res.

Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice: reduction in protective apoptotic response at the preneoplastic stage

EMBO J.

Bax suppresses tumorigenesis and stimulates apoptosis in vivo

Nature

Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis

Mol. Cell. Biol.

Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis

Science

p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa

Science

Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis

Review
Deconstructing p53 transcriptional networks in tumor suppression