Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer

Dávila, Mónica; Jhala, Darshana; Ghosh, Debashis; Grizzle, William E.; Chakrabarti, Ratna

doi:10.1186/1476-4598-6-40

Cited by 44 publications

(56 citation statements)

References 41 publications

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“…To minimize false-positive results, we compared normal and UL tissue taken from the same patients, thus reducing the chances of findings related to polymorphisms and menstrual cycle phases. Our results show that several genes, such as UHRF1, LIMK1, CALD1, MCM3 and others previously correlated with cancer (10)(11)(12), were upregulated in a fraction of the analyzed myomas. However, this fraction of overexpressed genes is very small, indicating that although they may contribute to tumor biology, they are not essential to tumorigenic pathology.…”

Section: Discussionmentioning

confidence: 59%

SPARC-like1 mRNA is overexpressed in human uterine leiomyoma

Mencalha

Levinsphul²,

Deterling³

et al. 2008

Mol Med Report

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Abstract. Uterine leiomyomas (ULs), also known as fibroids, are benign and monoclonal tumors frequently found in the female population. The genetic alterations that contribute to UL tumor development have not been well established, and the goal of this study was to reveal gene expression variation between ULs and healthy uterine tissue. We compared the gene expression profiles of 13 UL tumors with that of their adjacent normal tissue using the Differential Display mRNA assay (DDRT-PCR). Among the genes upregulated in some of the UL samples, several genes previously described in the context of cancer were identified, namely LIMK1, MCM3 and UHRF1. In addition, we identified a cDNA present in UL samples from distinct patients, which was absent from their normal tissue. Direct sequencing of this cDNA revealed a human SPARC-like1 (SPARCL1) mRNA homology. Through semi-quantitative PCR, we demonstrated that SPARCL1 was upregulated in approximately 77% of UL samples, but was absent in normal tissue. Real-time PCR (QPCR) revealed that SPARCL1 expression was increased 5-fold in ULs compared to adjacent normal tissue. These results suggest that the SPARCL1 gene is involved in UL development.

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Section: Discussionmentioning

confidence: 59%

SPARC-like1 mRNA is overexpressed in human uterine leiomyoma

Mencalha

Levinsphul²,

Deterling³

et al. 2008

Mol Med Report

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“…23 Our recent studies have shown that altered expression of LIMK1 is associated with chromosomal abnormalities and spindle defects. 24 In this study, we identified that the activated (phosphorylated) form of LIMK1/2 was localized in the mitotic apparatus in a mitotic phase-specific manner and that pLIMK1/2 in early phases of mitosis colocalized with g-tubulin. Our results provide novel information on possible association between a LIM motif containing kinase and centrosomal proteins.…”

Section: Introductionmentioning

confidence: 76%

Phosphorylated LIM Kinases Colocalize with Gamma-Tubulin in Centrosomes During Early Stages of Mitosis

Chakrabarti¹,

Jones²,

Oelschlager³

et al. 2007

Cell Cycle

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LIM kinases (LIMK1 and LIMK2) are LIM domain containing serine/threonine kinases that modulate reorganization of actin cytoskeleton through inactivating phosphorylation of cofilin. The Rho family of small GTPases regulates the catalytic activity of LIMK1 and LIMK2 through activating phosphorylation by ROCK or by p21 kinase. Recent studies have suggested that LIMK1 could play a role in modulation of cellular growth by alteration of the cell cycle in breast and prostate tumor cells; however, the direct mitogenic effects of LIMK1 in these tumor cells is yet to be elucidated. Via immunofluorescence, in this study, we show that phosphorylated LIM kinases (pLIMK1/2) are colocalized with g-tubulin in the centrosomes during the early mitotic phases of human breast and prostate cancer cells (MDA-MB-231 and DU145); apparent colocalization begins in the centrosomes in prophase. As shown by both bright field (MDA-MB-231) and fluorescent immunohistochemistry (MDA-MB-231 and DU145), pLIMK1/2 does not localize to centrosomes during interphase. By bright field immunohistochemistry, the largest area of the centrosome that is stained with pLIMK1/2 occurs at anaphase. In early telophase, reduced staining of pLIMK1/2 at the spindle poles and concomitant accumulation of pLIMK1/2 at the cleavage furrow begins to occur. In late telophase, loss of staining of pLIMK1/2 and of colocalization with g-tubulin occurs at the poles and pLIMK1/2 became further concentrated at the junction between the two daughter cells. Co-immunoprecipitation studies indicated that g-tubulin associates with phosphorylated LIMK1 and LIMK2 but not with dephosphorylated LIMK1 or LIMK2. The results suggest that activated LIMK1/2 may associate with g-tubulin and play a role in mitotic spindle assembly.

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“…The molecular mechanism(s) of how LIMK2 regulates mitosis and its knockdown induces mitotic spindle abnormalities still remains to be determined. Sumi et al (2006), suggested that LIMK2 and LIMK1 are required for spindle organization and chromosome segregation and recent studies have confirmed the role of cofilin phosphorylation by LIMK1 in this process (Davila et al, 2007;Kaji et al, 2008). LIMK2 is localized to the mitotic spindle during metaphase and early anaphase and then redistributed to the spindle midzone and co-localized with midzone microtubules during anaphase and telophase in HeLa cells (Sumi et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

LIM-kinase 2, a regulator of actin dynamics, is involved in mitotic spindle integrity and sensitivity to microtubule-destabilizing drugs

et al. 2009

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LIM-kinase 2 (LIMK2) belongs to the LIMK family of proteins, which comprises LIMK1 and LIMK2. Both proteins regulate actin polymerization through phosphorylation and inactivation of the actin depolymerizing factor cofilin. In this study, we show that the level of LIMK2 protein is increased in neuroblastoma, BE(2)-C cells, selected for resistance to microtubule-destabilizing agents, vincristine and colchicine. However, the level of phosphorylated LIMK1 and LIMK2 was similar in the resistant and parental BE(2)-C cells. In contrast, the level of phospho-cofilin was greatly increased in the drugresistant cells. Downregulation of LIMK2 expression increases sensitivity of neuroblastoma SH-EP cells to vincristine and vinblastine but not to microtubule-stabilizing agents, while it's overexpression increased its resistance to vincristine. Its vincristine-induced mitotic arrest was moderately inhibited in the LIMK2 knockdown cells, suggesting that the increased drug sensitivity is through an alternative mechanism other then mitotic arrest and apoptosis. Moreover, downregulation of LIMK2 expression induces formation of abnormal mitotic spindles, an effect enhanced in the presence of microtubule-destabilizing agents. LIMK2 is important for normal mitotic spindle formation and altered LIMK2 expression mediates sensitivity to microtubule destabilizing agents. These findings suggest that inhibition of LIMK2 activity may be used for the treatment of tumors resistant to microtubuledestabilizing drugs.

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Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer

Cited by 44 publications

References 41 publications

SPARC-like1 mRNA is overexpressed in human uterine leiomyoma

SPARC-like1 mRNA is overexpressed in human uterine leiomyoma

Phosphorylated LIM Kinases Colocalize with Gamma-Tubulin in Centrosomes During Early Stages of Mitosis

LIM-kinase 2, a regulator of actin dynamics, is involved in mitotic spindle integrity and sensitivity to microtubule-destabilizing drugs

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