Ran on tracks – cytoplasmic roles for a nuclear regulator

Yudin, Dmitry; Fainzilber, Mike

doi:10.1242/jcs.015289

Cited by 90 publications

(73 citation statements)

References 39 publications

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“…Similarly, PIKE (AGAP2/Centaurin-g1) was also found within nuclei (Dunphy et al, 2007). In addition, small GTP-binding proteins of the Ran family are best known for their crucial roles in the regulation of nucleocytoplasmic transport and in the function of mitotic spindle (Yudin and Fainzilber, 2009). Similar to other small G proteins, ARF1 may regulate processes in the nucleus, Golgi and at the plasma membrane.…”

Section: Discussionmentioning

confidence: 98%

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

et al. 2011

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The ADP-ribosylation factors (ARFs) 1 and 6 are small GTP-binding proteins, highly expressed and activated in several breast cancer cell lines and are associated with enhanced migration and invasiveness. In this study, we report that ARF1 has a critical role in cell proliferation. Depletion of this GTPase or expression of a dominant negative form, which both resulted in diminished ARF1 activity, led to sustained cell-growth arrest. This cellular response was associated with the induction of senescent markers in highly invasive breast cancer cells as well as in control mammary epithelial cells by a mechanism regulating retinoblastoma protein (pRB) function. When examining the role of ARF1, we found that this GTPase was highly activated in normal proliferative conditions, and that a limited amount could be found in the nucleus, associated with the chromatin of MDA-MB-231 cells. However, when cells were arrested in the G 0 /G 1 phase or transfected with a dominant negative form of ARF1, the total level of activated ARF1 was markedly reduced and the GTPase significantly enriched in the chromatin. Using biochemical approaches, we demonstrated that the GDP-bound form of ARF1 directly interacted with pRB, but not other members of this family of proteins. In addition, depletion of ARF1 or expression of ARF1T 31 N resulted in the constitutive association of pRB and E2F1, thereby stabilizing the interaction of E2F1 as well as pRB at endogenous sites of target gene promoters, preventing expression of E2F target genes, such as cyclin D1, Mcm6 and E2F1, important for cell-cycle progression. These novel findings provide direct physiological and molecular evidence for the role of ARF1 in controlling cell proliferation, dependent on its ability to regulate pRB/E2F1 activity and gene expression for enhanced proliferation and breast cancer progression.

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Section: Discussionmentioning

confidence: 98%

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

et al. 2011

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“…The higher relative levels of GTP-bound Ran in the nucleus facilitate the binding of Crm1 to the NES for export, and the GTP to GDP nucleotide exchange in the cytoplasm allows the dissociation of Crm1 from NES (Cook et al, 2007;Yudin and Fainzilber, 2009). To investigate Ran requirement for STAT5a nuclear export, cellular localization of STAT5a was evaluated in the presence of wild type Ran or a constitutively active Ran mutant Q69L that remains in a GTP-bound state (Bischoff et al, 1994;Klebe et al, 1995).…”

Section: Stat5a Nuclear Trafficking 3337mentioning

confidence: 99%

Dynamic Trafficking of STAT5 Depends on an Unconventional Nuclear Localization Signal

Shin

Reich

2013

Journal of Cell Science

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SummarySignal transducer and activator of transcription 5 (STAT5) is crucial for physiological processes that include hematopoiesis, liver metabolism and mammary gland development. However, aberrant continual activity of STAT5 has been causally linked to human leukemias and solid tumor formation. As a regulated transcription factor, precise cellular localization of STAT5 is essential. Conventional nuclear localization signals consist of short stretches of basic amino acids. In this study, we provide evidence that STAT5 nuclear import is dependent on an unconventional nuclear localization signal that functions within the conformation of an extensive coiled-coil domain. Both in vitro binding and in vivo functional assays reveal that STAT5 nuclear import is mediated by the importin-a3/ b1 system independently of STAT5 activation by tyrosine phosphorylation. The integrity of the coiled-coil domain is essential for STAT5 transcriptional induction of the b-casein gene following prolactin stimulation as well as its ability to synergize with the glucocorticoid receptor. The glucocorticoid receptor accumulates in the nucleus in response to prolactin and this nuclear import is dependent on STAT5 nuclear import. STAT5 continually shuttles in and out of the nucleus and live cell imaging demonstrates that STAT5 nuclear export is mediated by both chromosome region maintenance 1 (Crm1)-dependent and Crm1-independent pathways. A Crm1-dependent nuclear export signal was identified within the STAT5 N-terminus. These findings provide insight into the fundamental mechanisms that regulate STAT5 nuclear trafficking and cooperation with the glucocorticoid receptor and provide a basis for clinical intervention of STAT5 function in disease.

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“…Compartmentalization of RanGTP has been well studied in the context of nuclear transport, where the high concentration of RanGTP in the nucleus controls the polarity of transport [Yudin and Fainzilber, 2009]. A similar chromatin-proximal increase in RanGTP after nuclear envelope breakdown has been proposed to promote spindle assembly by activating various microtubule-regulatory proteins [reviewed by Dumont and Desai, 2012].…”

Section: The Molecular Signal Carried By Chromosomesmentioning

confidence: 99%

Polar body cytokinesis

2012

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Polar body cytokinesis is the physical separation of a small polar body from a larger oocyte or ovum. This maternal meiotic division shares many similarities with mitotic and spermatogenic cytokinesis, but there are several distinctions, which will be discussed in this review. We synthesize results from many different model species, including those popular for their genetics and several that are more obscure in modern cell biology. The site of polar body division is determined before anaphase, by the eccentric, cortically associated meiotic spindle. Depending on the species, either the actin or microtubule cytoskeleton is required for spindle anchoring. Chromatin is necessary and sufficient to elicit differentiation of the associated cortex, via Ran-based signaling. The midzone of the anaphase spindle serves as a hub for regulatory complexes that elicit Rho activation, and ultimately actomyosin contractile ring assembly and contraction. Polar body cytokinesis uniquely requires another Rho family GTPase, Cdc42, for dynamic reorganization of the polar cortex. This is perhaps due to the considerable asymmetry of this division, wherein the polar body and the oocyte/ovum have distinct fates and very different sizes. Thus, maternal meiotic cytokinesis appears to occur via simultaneous polar relaxation and equatorial contraction, since the polar body is extruded from the spherical oocyte through the nascent contractile ring. As such, polar body cytokinesis is an interesting and important variation on the theme of cell division. V C 2012 Wiley Periodicals, Inc

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Ran on tracks – cytoplasmic roles for a nuclear regulator

Cited by 90 publications

References 39 publications

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

Dynamic Trafficking of STAT5 Depends on an Unconventional Nuclear Localization Signal

Polar body cytokinesis

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