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

Wang, Lei; Yang, Linda; Debidda, Marcella; Witte, David P.; Zheng, Yi

doi:10.1073/pnas.0609149104

Cited by 116 publications

(125 citation statements)

References 35 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…The current Cdc42 conditional knockout model reveals unique HSC regulatory functions of Cdc42 that are not predictable in the Cdc42 gain-of-activity Cdc42GAP Ϫ/Ϫ mice (13,23,24). Although Cdc42GAP Ϫ/Ϫ hematopoietic progenitors show normal cell cycle progression but increased apoptosis due to increased JNK activity, Cdc42 Ϫ/Ϫ HSCs display drastically increased cell cycle progression/entry but unaltered survival property.…”

Section: Resultsmentioning

confidence: 99%

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Yang¹,

Wang²,

Geiger³

et al. 2007

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

Self Cite

167

164

View full text Add to dashboard Cite

Adult hematopoietic stem cells (HSCs) exist in a relatively quiescent state in the bone marrow (BM) microenvironment to fulfill longterm self-renewal and multilineage differentiation functions, an event that is tightly regulated by extrinsic and intrinsic cues. However, the mechanism coordinating the quiescent state of HSCs and their retention in the BM microenvironment remains poorly understood. In a conditional-knockout mouse model, we show that Cdc42 ؊/؊ HSCs enter the active cell cycle, resulting in significantly increased number and frequency of the stem/progenitor cells in the BM. Cdc42 deficiency also causes impaired adhesion, homing, lodging, and retention of HSCs, leading to massive egress of HSCs from BM to distal organs and peripheral blood and to an engraftment failure. These effects are intrinsic to the HSCs and are associated with deregulated c-Myc, p21 Cip1 , ␤1-integrin, and Ncadherin expressions and defective actin organization. Thus, Cdc42 is a critical coordinator of HSC quiescence maintenance and interaction with the BM niche.bone marrow microenvironment ͉ cell cycle ͉ adhesion A dult hematopoietic stem cells (HSCs) exist in a relatively quiescent state in the bone marrow (BM) microenvironment to execute long-term self-renewal and multilineage differentiation functions (1-3). The maintenance of HSC quiescence involves both extrinsic and intrinsic mechanisms. A number of genes that encode cell cycle or transcriptional regulators, including p21 Cip1 , p27 Kip1 , ␤-catenin/axin, cyclin D1, and c-Myc (4, 5), have been shown to regulate the intrinsic programs of HSCs in this process. In addition, interactions of HSCs with the BM microenvironment in specific anatomical and functional areas, referred to as niches, in the maintenance of HSC quiescence have also gained increasing recognition (6). One hypothesis is that the intrinsic and extrinsic cues, such as bone morphogenic proteins, Ca 2ϩ , Notch ligands, and/or Ang-1/Tie2 (7-10), in the BM microenvironment may coordinately regulate the HSC quiescent state.Despite of the identification of these molecular factors in HSCs and in BM that may collectively contribute to the maintenance of quiescence (7), the mechanism coordinating HSC cell cycle regulation and niche interaction remains unclear. Cdc42 is a ubiquitously expressed member of the Rho GTPase family involved in the regulation of multiple cell functions, including actin polymerization, cell-to-cell or cell-to-extracellular matrix adhesion, and gene transcription (11). Although its function has been extensively studied in various cell systems by expression of dominant negative or constitutively active mutants (12), the physiological roles of Cdc42 in most primary cell lineages, particularly in HSCs, remain unclear. Previously, in a gain-of-Cdc42 activity, Cdc42GAP Ϫ/Ϫ mouse model, we have found that constitutively increased Cdc42-GTP species cause increased hematopoietic progenitor apoptosis, disorganized actin structure, and defective engraftment without affecting the cell cycle status (13). T...

show abstract

Section: Resultsmentioning

confidence: 99%

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Yang¹,

Wang²,

Geiger³

et al. 2007

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

Self Cite

167

164

View full text Add to dashboard Cite

show abstract

“…ARHGAP1 codes for a Rho GTPase-activating protein 1, also known as Cdc42 GTPase-activating protein. It was shown that CDC42GAP-null mice also develop a senescence phenotype (Wang et al 2007). …”

Section: Pleiotropymentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

View full text Add to dashboard Cite

Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.

show abstract

“…However, in recent years a number of papers have appeared, particularly those involving prematurely aging mouse models, that implicate p53 in the regulation of some aging phenotypes (Lim et al, 2000;Tyner et al, 2002;Cao et al, 2003;Wong et al, 2003;Maier et al, 2004;Varela et al, 2005;Baker et al, 2006;Wang et al, 2007). In 2002, our laboratory described a genetically engineered mutant p53 mouse model (p53+/m) that exhibited an enhanced resistance to cancer that was accompanied by reduced longevity and premature onset of a number of aging phenotypes (Tyner et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity

Moore

Ghebranious

et al. 2007

Mechanisms of Ageing and Development

View full text Add to dashboard Cite

Evidence has accumulated that p53, a prototypical tumor suppressor, may also influence aspects of organismal aging. We have previously described a p53 mutant mouse model, the p53+/m mouse, which is cancer resistant yet exhibits reduced longevity and premature aging phenotypes. p53+/m mice express one full length p53 allele and one truncated p53 allele that is translated into a C-terminal fragment of p53 termed the M protein. The augmented cancer resistance and premature aging phenotypes in the p53+/m mice are consistent with a hyperactive p53 state. To determine how the M protein could increase p53 activity, we examined the M protein in various cellular contexts. Here, we show that embryo fibroblasts from p53+/m mice exhibit reduced proliferation and cell cycle progression compared to embryo fibroblasts from p53+/− mice (with equivalent wild-type p53 dosage). The M protein interacts with wild-type p53, increases its stability, and facilitates its nuclear localization in the absence of stress. Despite increasing p53 stability, the M protein does not disrupt p53-Mdm2 interactions and does not prevent p53 ubiquitination. These results suggest molecular mechanisms by which the M protein could influence the aging and cancer resistance phenotypes in the p53+/m mouse.

show abstract

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

Cited by 116 publications

References 35 publications

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity

Contact Info

Product

Resources

About