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

Authors: Wang L; Yang L; Debidda M; Witte D; Zheng Y

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, p16Ink4a, p21Cip1, and senescence-associated beta-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.

Keywords: Aging, Premature/*physiopathology; Animals; Cells, Cultured; *Genomic Instability; Karyotyping; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Tumor Suppressor Protein p53/genetics/physiology; cdc42 GTP-Binding Protein/*genetics
Journal: Proceedings of the National Academy of Sciences of the United States of America
Volume: 104
Issue: 4
Pages: 1248-53
Date: Jan. 18, 2007
PMID: 17227869
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Citation:

Wang L, Yang L, Debidda M, Witte D, Zheng Y (2007) Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes. Proceedings of the National Academy of Sciences of the United States of America 104: 1248-53.


Study Lifespan Factors:
  • Arhgap1 Rho GTPase activating protein 1


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