Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes

doi:10.1073/pnas.0609149104

Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes

Divisions of Experimental Hematology and Pathology, Molecular Developmental Biology Graduate Program, Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45229

Edited by Frederick W. Alt, Harvard Medical School, Boston, MA, and approved November 28, 2006 (received for review October 16, 2006)

Abstract

Cdc42 is a member of the Rho GTPase family known to regulate cell actin cytoskeleton organization, polarity, and growth, but its function in mammalian organismal physiology remains unclear. We found that natural aging of WT mice is marked with increased Cdc42 activity in various tissues. Among the negative regulators of Cdc42, gene targeting of Cdc42 GTPase-activating protein (Cdc42GAP) results in constitutively elevated Cdc42-GTP level in diverse tissues of adult mice; significantly shortened life span of the animals; and multiple premature aging-like phenotypes, including a reduction in body mass, a loss of subdermal adipose tissue, severe lordokyphosis, muscle atrophy, osteoporosis, and reduction of reepithelialization ability in wound-healing. Cdc42GAP^−/− mouse embryonic fibroblasts and/or tissues display reduced population doubling, significantly dampened DNA damage repair activity after DNA-damaging agent treatment, accumulated genomic abnormalities, and induction of p53, p16^Ink4a, p21^Cip1, and senescence-associated β-galactosidase expressions. Furthermore, Cdc42 activation is sufficient to promote a premature cellular senescence phenotype that depends on p53. These results suggest a role of Cdc42 activity in regulating mammalian genomic stability and aging-related physiology.

Footnotes

*To whom correspondence should be addressed at:
Division of Experimental Hematology, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229.
E-mail: yi.zheng{at}cchmc.org
Author contributions: L.W. and Y.Z. designed research; L.W., L.Y., M.D., D.W., and Y.Z. performed research; L.W., L.Y., and Y.Z. contributed new reagents/analytic tools; L.W., L.Y., D.W., and Y.Z. analyzed data; and L.W. and Y.Z. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0609149104/DC1.
Abbreviations:

GAP,

GTPase-activating protein;

MEF,

mouse embryonic fibroblast;

ROS,

reactive oxygen species;

SA-β-gal,

senescence-associated β-galactosidase.