RASSF1A interacts with and activates the mitotic kinase Aurora-A.
The RAS association domain family 1A (RASSF1A) gene is located at chromosome 3p21.3 within a specific area of common heterozygous and homozygous deletions. RASSF1A frequently undergoes promoter methylation-associated inactivation in human cancers. Rassf1a(-/-) mice are prone to both spontaneous and carcinogen-induced tumorigenesis, supporting the notion that RASSF1A is a tumor suppressor. However, it is not fully understood how RASSF1A is involved in tumor suppression pathways. Here we show that overexpression of RASSF1A inhibits centrosome separation. RASSF1A interacts with Aurora-A, a mitotic kinase. Surprisingly, knockdown of RASSF1A by siRNA led to reduced activation of Aurora-A, whereas overexpression of RASSF1A resulted in increased activation of Aurora-A, suggesting that RASSF1A is involved in Aurora-A activation. Like other Aurora-A activators, RASSF1A was also a substrate of Aurora-A in vitro. The failure of recombinant RASSF1A to activate recombinant Aurora-A indicates that RASSF1A may not activate Aurora-A directly and suggests that RASSF1A may function as a scaffold to bring together Aurora-A and its activator(s). Inhibition of centrosome separation by RASSF1A overexpression is most likely a consequence of hyperstabilization of microtubules by this protein.
Liu
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Division of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, CA 91010, USA.
Guo
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C
Dammann
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R
Tommasi
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Pfeifer
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GP
D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D019556:COS Cells; D018385:Centrosome / Q000737:chemistry; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
C411762:RASSF1 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases