Deficiency in myosin light-chain phosphorylation causes cytokinesis failure and multipolarity in cancer cells

Wu, Qian; Sahasrabudhe, Ruta; Luo, Li; Lewis, Dale; Gollin, Susanne M.; Saunders, William S.

doi:10.1038/onc.2010.165

Cited by 40 publications

(34 citation statements)

References 36 publications

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“…Consistently, the secondary hub enlargement defect in nos > H3T3D testes was also suppressed (Figure 7W). These findings are reminiscent of published studies in which expression of a phospho-mimic substrate can rescue the phenotypes of compromised kinase activity in cancer cells (Wu et al, 2010). Together, the opposite genetic interactions between haspin and the two H3 mutations on T3 further support the hypothesis that H3T3P needs to be tightly controlled for proper H3 inheritance and germline activity.…”

Section: Resultssupporting

confidence: 68%

Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline

Xie

Wooten

Tran

et al. 2015

Cell

120

126

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SUMMARY A long-standing question concerns how stem cells maintain their identity through multiple divisions. Previously we reported that pre-existing and newly synthesized histone H3 are asymmetrically distributed during Drosophila male germline stem cell (GSC) asymmetric division. Here we show that phosphorylation at Threonine 3 of H3 (H3T3P) distinguishes preexisting versus newly synthesized H3. Converting T3 to the unphosphorylatable residue alanine (H3T3A) or to the phosphomimetic aspartate (H3T3D) disrupts asymmetric H3 inheritance. Expression of H3T3A or H3T3D specifically in early-stage germline also leads to cellular defects including GSC loss and germline tumors. Finally, compromising the activity of the H3T3 kinase Haspin enhances the H3T3A but suppresses the H3T3D phenotypes. Together these studies demonstrate that H3T3P distinguishes sister chromatids enriched with distinct pools of H3, coordinating asymmetric segregation of “old” H3 into GSCs, and that a tight regulation of H3T3 phosphorylation is required for male germline activity.

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Section: Resultssupporting

confidence: 68%

Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline

Xie

Wooten

Tran

et al. 2015

Cell

120

126

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“…Increasing evidence suggests that myosins play essential roles in cases of cytokinesis failure [58], chromosomal and centrosomal amplification [59], multipolar spindle formation [55] and DNA microsatellite instability [36]. Identifying myosins' specific functions and clarifying their related mechanisms have become a prime focus in oncology.…”

Section: Effects Of Myosins On Genetic or Chromosomal Instabilitymentioning

confidence: 99%

“…Wu et al [59] found that cancer cells always failed at cytokinesis because of reduced phosphorylation of the myosin regulatory light chain (MLC). This limited MLC phosphorylation level was correlated with the overexpression of myosin phosphatase (MYPT1) and decreased expression of myosin light chain kinase (MLCK).…”

Section: Effects Of Myosins On Genetic or Chromosomal Instabilitymentioning

confidence: 99%

Myosins as fundamental components during tumorigenesis: diverse and indispensable

Yang

2016

Oncotarget

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Myosin is a kind of actin-based motor protein. As the crucial functions of myosin during tumorigenesis have become increasingly apparent, the profile of myosin in the field of cancer research has also been growing. Eighteen distinct classes of myosins have been discovered in the past twenty years and constitute a diverse superfamily. Various myosins share similar structures. They all convert energy from ATP hydrolysis to exert mechanical stress upon interactions with microfilaments. Ongoing research is increasingly suggesting that at least seven kinds of myosins participate in the formation and development of cancer. Myosins play essential roles in cytokinesis failure, chromosomal and centrosomal amplification, multipolar spindle formation and DNA microsatellite instability. These are all prerequisites of tumor formation. Subsequently, myosins activate various processes of tumor invasion and metastasis development including cell migration, adhesion, protrusion formation, loss of cell polarity and suppression of apoptosis. In this review, we summarize the current understanding of the roles of myosins during tumorigenesis and discuss the factors and mechanisms which may regulate myosins in tumor progression. Furthermore, we put forward a completely new concept of “chromomyosin” to demonstrate the pivotal functions of myosins during karyokinesis and how this acts to optimize the functions of the members of the myosin superfamily.

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“…These results were somewhat expected, because disruption of MLC2 phosphorylation caused multipolar spindles and cytokinesis failure in cancer cells. 25 It was also reported that expression of unphosphorylated MLC2 in mammalian cells caused failure of cytokinesis. 26 Thus, our result suggested that MLC2 phosphorylation may positively affect polar body extrusion in mouse oocytes meiosis.…”

Section: Discussionmentioning

confidence: 99%

RhoA-mediated MLC2 regulates actin dynamics for cytokinesis in meiosis

Duan

Zhu

et al. 2016

Cell Cycle

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During oocyte meiosis, the bipolar spindle forms in the central cytoplasm and then migrates to the cortex. Subsequently, the oocyte extrudes the polar body through two successive asymmetric divisions, which are regulated primarily by actin filaments. Myosin light chain2 (MLC2) phosphorylation plays pivotal roles in smooth muscle contraction, stress fiber formation, cell motility and cytokinesis. However, whether MLC2 phosphorylation participates in the oocyte polarization and asymmetric division has not been clarified. The present study investigated the expression and functions of MLC2 during mouse oocyte meiosis. Our result showed that p-MLC2 was localized in the oocyte cortex, with a thickened cap above the chromosomes. Meanwhile, p-MLC2 was also localized in the poles of spindle. Disruption of MLC2 activity by MLC2 knock down (K D ) caused the failure of polar body extrusion. Immunofluorescent staining showed that a large proportion of oocytes arrested in telophase stage and failed to undergo cytokinesis after culturing for 12 hours. In the meantime, actin filament staining at oocyte membrane and cytoplasm were reduced in MLC2 K D oocytes. Finally, we found that the phosphorylation of MLC2 protein levels was decreased after disruption of RhoA activity. Above all, our data indicated that the RhoA-mediated MLC2 regulates the actin organization for cytokinesis during mouse oocyte maturation.

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Deficiency in myosin light-chain phosphorylation causes cytokinesis failure and multipolarity in cancer cells

Cited by 40 publications

References 36 publications

Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline

Histone H3 Threonine Phosphorylation Regulates Asymmetric Histone Inheritance in the Drosophila Male Germline

Myosins as fundamental components during tumorigenesis: diverse and indispensable

RhoA-mediated MLC2 regulates actin dynamics for cytokinesis in meiosis

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