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Document Type |
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Article In Journal |
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Document Title |
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RAN GTPase Is a RASSF1A Effector Involved in Controlling Microtubule Organization RAN GTPase Is a RASSF1A Effector Involved in Controlling Microtubule Organization |
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Document Language |
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English |
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Abstract |
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RASSF1A is a tumor suppressor gene that is inactivated by
hypermethylation of its promoter region in most types of
human cancers [1–3]. The incidence of spontaneous or
induced tumors is significantly higher in Rassf1a2/2 mice
than in wild-type mice, confirming the tumor suppressor
function of RASSF1A [4, 5]. RASSF1A promotes apoptosis
mainly through its interaction with the proapoptotic serine/
threonine STE20-like kinases MST1 and 2 [6, 7]. However,
Rassf1a2/2 mice do not show overt signs of deregulated
apoptosis [4, 5], suggesting that other RASSF1A effectors
are also critical for tumor suppression. In a proteomics
screen, we identified RAN GTPase, MST1 and 2 kinases,
and a- and g-tubulin as RASSF1A-interacting proteins. We
show that RASSF1A-induced microtubule hyperstability,
a hallmark of RASSF1A expression [8, 9], is RAN-GTP dependent.
RASSF1A promotes the accumulation of the GTPbound
form of RAN via the MST2-induced phosphorylation
of RCC1. Depletion of RASSF1A results in mislocalization of
RCC1 to the mitotic spindle and spindle poles, leading to
mitotic spindle abnormalities and prometaphase block. A
similar mitotic delay is also observed with MST2 depletion.
These findings reveal a mechanism for how RASSF1A
controls microtubule stability and for how its loss compromises
the integrity of the mitotic spindle, leading to aneuploidy
and tumorigenesis. |
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ISSN |
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1879-0445 |
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Journal Name |
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Current Biology |
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Volume |
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19 |
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Issue Number |
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14 |
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Publishing Year |
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1430 AH
2009 AD |
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Article Type |
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Article |
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Added Date |
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Monday, April 26, 2010 |
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Researchers
| أشرف دلول | Dallol, Ashraf | Investigator | Doctorate | a.dallol@bham.ac.uk |
| فريدة لطيف | Latif, Farida | Investigator | Doctorate | f.latif@bham.ac.uk |
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