Myeloproliferative Defects following Targeting of the <i>Drf1</i> Gene Encoding the Mammalian Diaphanous–Related Formin mDia1

Peng, Jun; Kitchen, Susan M.; West, Richard; Sigler, Robert E.; Eisenmann, Kathryn M.; Alberts, Arthur S.

doi:10.1158/0008-5472.can-07-1467

Cited by 86 publications

(75 citation statements)

References 20 publications

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“…These data suggested a potential role for loss of mDia1 function in the etiology of (del)5 or 5q-MDS. This led us to target the murine Drf1 gene for knockout (Peng et al, 2007); as previously published and described in detail below, Drf1 À/À mice developed an age-dependent myelodysplasia, similar in phenotype to other knockout mice targeting genes residing in the 5q CDRs, including EGR1 and RPS14. First, let us consider the 5q candidates historically associated with the (del)5 or 5q-subset of MDS.…”

Section: Cdrs In 5qmentioning

confidence: 88%

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

et al. 2009

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Section: Cdrs In 5qmentioning

confidence: 88%

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

et al. 2009

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“…Ϫ/Ϫ and WASp Ϫ/Ϫ mice were generated as previously described (21,22) and bred with one another to derive mDia1 Ϫ/Ϫ and WAS Ϫ/Ϫ mice. All mouse strains were maintained on the C57BL/6 background and under pathogen-free conditions at the Samuel Lunenfeld Animal Facility.…”

Section: Mice Mdia1mentioning

confidence: 99%

“…On the basis of immunoblotting analyses identifying mDia1 as the predominant mDia expressed in bone marrow neutrophils (Fig. 1A), we investigated the roles of mDia1 in neutrophil physiology using mDia1-deficient mice generated by targeted disruption of the Drf1 gene (22). Histological and cytological examination of 8-wkold mDial Ϫ/Ϫ mice revealed progressive bone marrow hypercellularity, reflecting an almost 2-fold increase in marrow neutrophil numbers (Fig.…”

Section: Mdia1 ϫ/ϫ Mice Manifest Expansion Of Bone Marrow and Splenicmentioning

confidence: 99%

The mDial Formin Is Required for Neutrophil Polarization, Migration, and Activation of the LARG/RhoA/ROCK Signaling Axis during Chemotaxis

Shi

Zhang

Mullin

et al. 2009

The Journal of Immunology

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Neutrophil chemotaxis depends on actin dynamics, but the roles for specific cytoskeleton regulators in this response remain unclear. By analysis of mammalian diaphanous-related formin 1 (mDia1)-deficient mice, we have identified an essential role for this actin nucleator in neutrophil chemotaxis. Lack of mDia1 was associated with defects in chemoattractant-induced neutrophil actin polymerization, polarization, and directional migration, and also with impaired activation of RhoA, its downstream target p160-Rho-associated coil-containing protein kinase (ROCK), and the leukemia-associated RhoA guanine nucleotide exchange factor (LARG). Our data also revealed mDia1 to be associated with another cytoskeletal regulator, Wiskott-Aldrich syndrome protein (WASp), at the leading edge of chemotaxing neutrophils and revealed polarized morphology and chemotaxis to be more mildly impaired in WAS ؊/؊ than in mDia1 ؊/؊ neutrophils, but essentially abrogated by combined mDia1/WASp deficiency. Thus, mDia1 roles in neutrophil chemotaxis appear to be subserved in concert with WASp and are realized at least in part by activation of the LARG/RhoA/ROCK signaling pathway.

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“…Formin proteins play a role in diverse processes such as cell migration (1,2), vesicle trafficking (3,4), tumor suppression (5,6), and microtubule stabilization (7,8). Formins also play an essential and conserved role in cytokinesis (9 -11).…”

mentioning

confidence: 99%

Ubiquitin-mediated Degradation of the Formin mDia2 upon Completion of Cell Division

DeWard

Alberts

2009

Journal of Biological Chemistry

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Formins assemble non-branched actin filaments and modulate microtubule dynamics during cell migration and cell division. At the end of mitosis formins contribute to the generation of actin filaments that form the contractile ring. Rho small GTPbinding proteins activate mammalian diaphanous-related (mDia) formins by directly binding and disrupting an intramolecular autoinhibitory mechanism. Although the Rho-regulated activation mechanism is well characterized, little is known about how formins are switched off. Here we reveal a novel mechanism of formin regulation during cytokinesis based on the following observations; 1) mDia2 is degraded at the end of mitosis, 2) mDia2 is targeted for disposal by post-translational ubiquitin modification, 3) forced expression of activated mDia2 yields binucleate cells due to failed cytokinesis, and 4) the cytokinesis block is dependent upon mDia2-mediated actin assembly as versions of mDia2 incapable of nucleating actin but that still stabilize microtubules have no effect on cytokinesis. We propose that the tight control of mDia2 expression and ubiquitin-mediated degradation is essential for the completion of cell division. Because of the many roles for formins in cell morphology, we discuss the relevance of mDia protein turnover in other processes where ubiquitin-mediated proteolysis is an essential component.

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Myeloproliferative Defects following Targeting of the Drf1 Gene Encoding the Mammalian Diaphanous–Related Formin mDia1

Cited by 86 publications

References 20 publications

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

The mDial Formin Is Required for Neutrophil Polarization, Migration, and Activation of the LARG/RhoA/ROCK Signaling Axis during Chemotaxis

Ubiquitin-mediated Degradation of the Formin mDia2 upon Completion of Cell Division

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