Identification of Aurora-A as a direct target of E2F3 during G2/M cell cycle progression.
Aurora-A is a centrosome kinase and plays a pivotal role in G(2)/M cell cycle progression. Expression of Aurora-A is cell cycle-dependent. Levels of Aurora-A mRNA and protein are low in G(1)/S, accumulate during G(2)/M, and decrease rapidly after mitosis. Previous studies have shown regulation of the Aurora-A protein level during the cell cycle through the ubiquitin-proteasome pathway. However, the mechanism of transcriptional regulation of Aurora-A remains largely unknown. Here, we demonstrated that E2F3 modulates Aurora-A mRNA expression during the cell cycle. Ectopic expression of E2F3 induces Aurora-A expression. Stable knockdown of E2F3 decreases mRNA and protein levels of Aurora-A and delays G(2)/M entry. Further, E2F3 directly binds to Aurora-A promoter and stimulates the promoter activity. Deletion and mutation analyses of the Aurora-A promoter revealed that a region located 96-bp upstream of the transcription initiation site is critical for the activation of the promoter by E2F3. In addition, expression of E2F3 positively correlates with the protein level of Aurora-A in human ovarian cancer examined. These results indicate for the first time that Aurora-A is transcriptionally regulated by E2F3 during the cell cycle and that E2F3 is a causal factor for up-regulation of Aurora-A in a subset of human ovarian cancer. Thus, the E2F3-Aurora-A axis could be an important target for cancer intervention.
He
Lili
L
Molecular Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 133612, USA.
Yang
Hua
H
Ma
Yihong
Y
Pledger
W Jack
WJ
Cress
W Douglas
WD
Cheng
Jin Q
JQ
D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016195:G2 Phase / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008677:Metaphase; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C490840:E2f3 protein, mouse; D009363:Neoplasm Proteins; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases
Int J Cancer. 2001 May 1;92(3):370-3
11291073
Oncogene. 2000 Jul 13;19(30):3422-33
10918599
Oncogene. 2004 Feb 26;23(8):1627-30
14716298
Lung Cancer. 2006 Nov;54(2):155-62
16938365
Cell Growth Differ. 1998 Aug;9(8):585-93
9716176
Genes Dev. 1998 Aug 1;12(15):2245-62
9694791
Mol Cell Biol. 2000 May;20(10):3626-32
10779352
Br J Cancer. 2001 Mar 23;84(6):824-31
11259099
EMBO J. 2004 Nov 24;23(23):4615-26
15510213
Clin Cancer Res. 2000 May;6(5):1833-9
10815905
J Biol Chem. 2003 Jun 27;278(26):23432-40
12697749
Nat Genet. 1998 Oct;20(2):189-93
9771714
Dev Cell. 2006 Aug;11(2):147-57
16890155
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15948-53
16249342
EMBO J. 2004 Dec 8;23(24):4709-16
15538380
Genetics. 1993 Nov;135(3):677-91
8293973
Mol Cell Biol. 2001 Jul;21(14):4684-99
11416145
Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9267-71
1409633
Mol Cell Biol. 1996 Mar;16(3):1047-57
8622649
Clin Cancer Res. 2003 Apr;9(4):1420-6
12684414
J Biol Chem. 2002 Mar 22;277(12):10719-26
11790771
Clin Cancer Res. 2003 Mar;9(3):991-7
12631597
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1357-61
7877982
Clin Cancer Res. 2004 May 15;10(10):3291-300
15161682
Oncogene. 1997 Jun 12;14(23):2793-801
9190895
Genes Dev. 2002 Jan 15;16(2):245-56
11799067
Oncogene. 2004 Aug 5;23(35):5871-9
15184867
Oncogene. 2002 Jan 17;21(3):437-46
11821956
J Biol Chem. 2006 May 26;281(21):14691-9
16574658
Nat Cell Biol. 2005 Oct;7(10):937-46
16184168
Science. 2002 May 10;296(5570):1132-6
12004135
Cell. 1998 Jun 26;93(7):1183-93
9657151
J Cell Biol. 2002 Aug 19;158(4):617-23
12177045
EMBO J. 1998 Jun 1;17(11):3052-65
9606188
Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7245-50
9207076
J Natl Cancer Inst. 2002 Sep 4;94(17):1320-9
12208897
Nat Rev Cancer. 2005 Jan;5(1):42-50
15630414
Genes Dev. 1998 Jul 15;12(14):2120-30
9679057
Methods. 2002 Jan;26(1):48-56
12054904
Oncogene. 2005 Jul 21;24(31):5000-4
15897886