Regulation of tumor suppressor RASSF1A in the cell cycle = 항암유전자 RASSF1A의 인산화를 통한 세포 주기 조절 기전 연구

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Here I show that RASSF1A serine 203 can be phosphorylated by Aurora kinases at spindle poles and spindles during mitosis, while the same residue is phosphorylated by cyclin D-Cdk4 in the nucleus during interphase. Theses data suggest that the RASSF1A phosphorylation by different kinases regulates the cell cycle in the specialized cellular compartments. Indeed, Aurora A-mediated RASSF1A phoshphorylation activates the mitotic ubiquitin ligase APC by inducing its dissociation from an APC activator Cdc20 during prometaphase. Paradoxically, RASSF1A itself can be also degraded by cyclin D-Cdk4-mediated phosphorylation followed by another ubiqutin ligase SCF-Skp2-dependent ubiquitination at the $G_1$-S transition. Since Human cancers often show overexpression of Aurora kinases, Skp2, cyclin D1 and high levels of Cdk4 activity, the diminishing RASSF1A activity by Aurora kinases, Skp2 or cyclin D-Cdk4 may contribute to tumorigenesis. Therefore, I had to divide this thesis into the Aurora kinases-RASSF1A story (PartI) and the SCF-Skp2-RASSF1A story (PartII). PART Ⅰ Abstract The Aurora (Ipl) family kinases play important role in regulation of mitosis in eukaryotes(Marumoto et al., 2005; Nigg, 2001). The tumor suppressor RASSF1A regulates mitotic progression by inhibiting anaphase-promoting complex (APC)-Cdc20 activity(Agathanggelou et al., 2005; Jackson, 2004; Song et al., 2004; Yu, 2007), but the regulation of this action has remained unknown. Here, we show that Aurora kinases associate with and phosphorylate RASSF1A on serine 203 in vivo during mitosis. Notably, both depletion of Aurora A by RNA interference (RNAi) and expression of the nonphosphorylatable S203A mutant of RASSF1A, which did not contribute to the spindle checkpoint activation, led to a marked delay in prometaphase progression beyond mitotic entry. This is likely due to the failure of dissociation of RASSF1A from Cdc20, the constitutive inhibition of APC-Cdc20 and the persistent accumulation of mit...
Lim, Dae-Sikresearcher임대식researcher
한국과학기술원 : 생명과학과,
Issue Date
310400/325007  / 020045133

학위논문(박사) - 한국과학기술원 : 생명과학과, 2008.2, [ viii, 118 p. ]


cell cycle regulation; tumor suppressor; RASSF1A; Aurora A; Skp2; 세포 주기 조절; 항암유전자; RASSF1A; Aurora A; Skp2; cell cycle regulation; tumor suppressor; RASSF1A; Aurora A; Skp2; 세포 주기 조절; 항암유전자; RASSF1A; Aurora A; Skp2

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