The F-actin severing protein cofilin-1 is required for RNA polymerase II transcription elongation

Obrdlík, Aleš; Percipalle, Piergiorgio

doi:10.4161/nucl.2.1.14508

Cited by 71 publications

(59 citation statements)

References 30 publications

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“…However, the lack of cofilin 1 in this cell line has a measurable impact on transcription (Fig. 6C), corroborating earlier findings that cofilin might play a direct role in RNA-polymerase-II-mediated transcription (42).…”

Section: Nuclear Export Of Actin Is Mediated By Exp6 and Is Not Sensisupporting

confidence: 79%

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Active maintenance of nuclear actin by importin 9 supports transcription

Dopie

Skarp

Rajakylä

et al. 2012

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

222

320

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Besides its essential and well established role as a component of the cytoskeleton, actin is also present in the cell nucleus, where it has been linked to many processes that control gene expression. For example, nuclear actin regulates the activity of specific transcription factors, associates with all three RNA polymerases, and is a component of many chromatin remodelling complexes. Despite the fact that two export receptors, Crm1 and exportin 6, have been linked to nuclear export of actin, the mechanism by which actin enters the nucleus to elicit these essential functions has not been determined. It is also unclear whether actin is actively exchanged between the nucleus and the cytoplasm, and whether this connection has any functional significance for the cell. By applying a variety of live-cell imaging techniques we revealed that actin constantly shuttles in and out of the nucleus. The fast transport rates, which depend on the availability of actin monomers, suggest an active transport mechanism in both directions. Importantly, we identified importin 9 as the nuclear import factor for actin. Furthermore, our RNAi experiments showed that the active maintenance of nuclear actin levels by importin 9 is required for maximal transcriptional activity. Measurements of nuclear export rates and depletion studies also clarified that nuclear export of actin is mediated by exportin 6, and not by Crm1. These results demonstrate that cytoplasmic and nuclear actin pools are dynamically connected and identify the nuclear import and export mechanisms of actin.

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Section: Nuclear Export Of Actin Is Mediated By Exp6 and Is Not Sensisupporting

confidence: 79%

“…Also cofilin-depleted cells showed reduced 5-FUrd incorporation as compared to control cells (Fig. 6B), as demonstrated previously (42). Interestingly, excess nuclear actin promoted by Exp6 depletion would slightly hinder transcription (Fig.…”

Section: Nuclear Export Of Actin Is Mediated By Exp6 and Is Not Sensisupporting

confidence: 68%

Active maintenance of nuclear actin by importin 9 supports transcription

Dopie

Skarp

Rajakylä

et al. 2012

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

222

320

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“…The cofilin sequence contains a nuclear localization signal (Iida et al, 1992), and nuclear cofilin-1 has been shown to regulate transcription elongation by controlling dynamics of gene-associated actin (Obrdlik and Percipalle, 2011). Thus, HMI-1a3-induced nuclear translocation of cofilin observed in this study may contribute to the prominent HMI-1a3-induced changes in gene expression.…”

Section: Discussionmentioning

confidence: 55%

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

Talman

Gateva

Ahti

et al. 2014

European Journal of Pharmaceutical Sciences

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Diacylglycerol (DAG) is a central mediator of signaling pathways that regulate cell proliferation, survival and apoptosis. Therefore, C1 domain, the DAG binding site within protein kinase C (PKC) and other DAG effector proteins, is considered a potential cancer drug target. Derivatives of 5-(hydroxymethyl)isophthalic acid are a novel group of C1 domain ligands with antiproliferative and differentiation-inducing effects. Our previous work showed that these isophthalate derivatives exhibit antiproliferative and elongation-inducing effects in HeLa human cervical cancer cells. In this study we further characterized the effects of bis(3-trifluoromethylbenzyl) 5-(hydroxymethyl)isophthalate (HMI-1a3) on HeLa cell proliferation and morphology. HMI-1a3-induced cell elongation was accompanied with loss of focal adhesions and actin stress fibers, and exposure to HMI-1a3 induced a prominent relocation of cofilin-1 into the nucleus regardless of cell phenotype. The antiproliferative and morphological responses to HMI-1a3 were not modified by coexposure to pharmacological inhibition or activation of PKC, or by RNAi knock-down of specific PKC isoforms, suggesting that the effects of HMI-1a3 were not mediated by PKC. Genome-wide gene expression microarray and gene set enrichment analysis suggested that, among others, HMI-1a3 induces changes in small GTPasemediated signaling pathways. Our experiments revealed that the isophthalates bind also to the C1 domains of β2-chimaerin, protein kinase D (PKD) and MRCK, which are potential mediators of small GTPase signaling and cytoskeletal reorganization. Pharmacological inhibition of MRCK, but not that of PKD attenuated HMI1a3-induced cell elongation, suggesting that MRCK participates in mediating the effects of HMI-1a3 on HeLa cell morphology.

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“…On the other hand, Obrdlik and Percipalle observed the same localization of 5-FUrd as in the present study, and related this staining with polymerase II RNA. They also showed that cofilin-1 was involved in the machinery of transcription of certain genes, in which interaction with actin was involved [46]. Additionally, they suggested that the controlled polymerization of actin may be important for polymerase II transcription.…”

Section: Discussionmentioning

confidence: 95%

The role of exportin 6 in cytoskeletal-mediated cell death and cell adhesion in human non-small-cell lung carcinoma cells following doxorubicin treatment

Izdebska

Gagat²,

Grzanka³

et al. 2014

Folia Histochem Cytobiol.

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Abstract:The actin cytoskeleton plays an important role in various cellular processes. The different forms of actin (G-actin and F-actin) participate in the organization of nuclear structure and its functions. The structure of the actin cytoskeleton is controlled by proteins involved in the translocation of actin between cytoplasm and the nucleus. In this study, we used siRNA method to investigate the role of exportin 6 in the switching between nuclear and cytoplasmic F-actin pools in H1299 cells treated with no, 1.0 or 2.5 µM doxorubicin. We showed that silencing of exportin 6 expression changed the response of H1299 to doxorubicin. Here, we observed increased population of cells affected by doxorubicin-induced necrotic cell death. Furthermore, fluorescence studies showed that downregulation of exportin 6 exerted profound DOX-induced changes in the F-actin cytoskeleton architecture. The F-actin cytoskeleton was seen in the form of small fibers or aggregates after doxorubicin treatment. Additionally, some cells lost cell adhesion properties. Downregulation of exportin 6 influenced also transcriptional activity of the cells. In cells transfected with nontargeting siRNA, we observed a higher level of 5'-fluorouridine fluorescence than in cells with silenced exportin 6 expression. In conclusion, we showed that downregulation of exportin 6 induced necrotic cell death. Moreover, the observed alterations of cell adhesion suggest the key role of cytoplasmic F-actin in maintaining intercellular junctional complexes and/or focal adhesion properties and the importance of the balance between nuclear and cytoplasmic F-actin pools.

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The F-actin severing protein cofilin-1 is required for RNA polymerase II transcription elongation

Cited by 71 publications

References 30 publications

Active maintenance of nuclear actin by importin 9 supports transcription

Active maintenance of nuclear actin by importin 9 supports transcription

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

The role of exportin 6 in cytoskeletal-mediated cell death and cell adhesion in human non-small-cell lung carcinoma cells following doxorubicin treatment

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