Cdc42GAP regulates c-Jun N-terminal kinase (JNK)-mediated apoptosis and cell number during mammalian perinatal growth

Wang, Lei; Yang, Linda; Burns, Kevin A.; Kuan, Chia-Yi; Zheng, Yi

doi:10.1073/pnas.0504420102

Cited by 49 publications

(63 citation statements)

References 32 publications

(40 reference statements)

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“…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%

“…Because HSCs need to detach from the niche where they are maintained at a quiescent state and migrate to a proliferative zone to enter into asymmetric division and expansion (23), it is believed that HSC interaction with the niche microenvironment and HSC quiescent state maintenance are closely interconnected. The present study shows that deletion of Cdc42 reduces the number and frequency of quiescent HSCs and increases the stem/progenitor population that is actively cycling.…”

Section: Resultsmentioning

confidence: 99%

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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.

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167

164

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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...

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Section: Resultsmentioning

confidence: 99%

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

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“…In primary MEFs, however, Cdc42 activity is critical for cell proliferation, as loss or gain of activity of Cdc42 affects cell cycle progression and/or survival ( Figure 7; Wang et al, 2005). The cell growth defects of the Cdc42 Ϫ/Ϫ cells correlate with defects in ERK1/2, JNK, and/or p70S6K activity, and with a defect in transcriptional activation of NF-B (Figures 8 and 9).…”

Section: Discussionmentioning

confidence: 99%

Gene Targeting of Cdc42 and Cdc42GAP Affirms the Critical Involvement of Cdc42 in Filopodia Induction, Directed Migration, and Proliferation in Primary Mouse Embryonic Fibroblasts

Yang

Wang

Zheng

2006

MBoC

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138

129

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“…Interestingly, those few studies commonly reported that the ablation of a specific GAP resulted in the global elevation of the activity of the target small GTPase (49,57,58); Rho GTP levels were highly elevated in P190B RhoGAP null murine embryonic fibroblasts (49), as was the Cdc42 GTP level in Cdc42GAP null murine embryonic fibroblasts and hematopoietic stem cells (57,58). Those studies also reported changes in the overall size of the cells or the whole animal as well as in the growth of cells (49,57,58). However, we did not see any difference in basal Rac GTP levels among bcr Ϫ/Ϫ , abr Ϫ/Ϫ , and (abr ϫ bcr) Ϫ/Ϫ BMMs, nor did we observe any change in the overall cell size of BMMs or the whole animal (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Abr and Bcr, Two Homologous Rac GTPase-Activating Proteins, Control Multiple Cellular Functions of Murine Macrophages

Cho

Cunnick²,

Yi³

et al. 2007

Molecular and Cellular Biology

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Cdc42GAP regulates c-Jun N-terminal kinase (JNK)-mediated apoptosis and cell number during mammalian perinatal growth

Cited by 49 publications

References 32 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

Gene Targeting of Cdc42 and Cdc42GAP Affirms the Critical Involvement of Cdc42 in Filopodia Induction, Directed Migration, and Proliferation in Primary Mouse Embryonic Fibroblasts

Abr and Bcr, Two Homologous Rac GTPase-Activating Proteins, Control Multiple Cellular Functions of Murine Macrophages

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