Negative feedback regulation of Aurora-A via phosphorylation of Fas-associated factor-1.
This study reports that Aurora-A (Aur-A) phosphorylates Fas-associated factor-1 (FAF1) at Ser-289 and Ser-291. Forced expression of a FAF1 mutant mimicking phosphorylation at Ser-289 and Ser-291 (FAF1 DD), but not phosphorylation-deficient FAF1 (FAF1 AA), reduced Aur-A expression. However, transfection of FAF1 DD failed to reduce Aur-A expression in the presence of MG132 and MG115, indicating that this decrease is proteasome-mediated. Additionally, transfection of FAF1 DD suppressed the expression of Aur-A in ts20-BALB cells lacking E1 ubiquitin (Ub) activating enzyme activity at restrictive temperatures and also reduced the expression of Aur-A S51D, a mutant resistant to Ub-dependent degradation. Our data indicate that phosphorylated FAF1 mediates the ubiquitin-independent, proteasome-dependent degradation of Aur-A. Overexpression of FAF1 DD blocked Aur-A-induced centrosome amplification and accumulated cells in G(2)/M phase, representing cellular phenotypes consistent with the anticipated loss of Aur-A. Collectively, our findings support the negative feedback regulation of Aur-A via phosphorylation of the death-promoting protein, FAF1, and disclose the presence of molecular cross-talk between constituents of the cell cycle and cell death machinery.
Jang
Moon-Sun
MS
Department of Biology, Chungnam National University, Daejeon 305-764, Korea.
Sul
Jee-Won
JW
Choi
Byung-Jung
BJ
Lee
Su-Jin
SJ
Suh
Jee-Hee
JH
Kim
Nam-Soon
NS
Kim
Woo Ho
WH
Lim
Dae-Sik
DS
Lee
Chang-Woo
CW
Kim
Eunhee
E
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000502:physiology; D034622:RNA Interference
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C490780:FAF1 protein, human; C097186:Faf1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex