title: PAX8 promotes tumor cell growth by transcriptionally regulating E2F1 and stabilizing RB protein.
abstract: The retinoblastoma protein (RB)-E2F1 pathway has a central role in regulating the cell cycle. Several PAX proteins (tissue-specific developmental regulators), including PAX8, interact with the RB protein, and thus regulate the cell cycle directly or indirectly. Here, we report that PAX8 expression is frequent in renal cell carcinoma, bladder, ovarian and thyroid cancer cell lines, and that silencing of PAX8 in cancer cell lines leads to a striking reduction in the expression of E2F1 and its target genes, as well as a proteasome-dependent destabilization of RB protein, with the RB1 mRNA level remaining unaffected. Cancer cells expressing PAX8 undergo a G(1)/S arrest and eventually senesce following PAX8 silencing. We demonstrate that PAX8 transcriptionally regulates the E2F1 promoter directly, and E2F1 transcription is enhanced after RB depletion. RB is recruited to the PAX8-binding site, and is involved in PAX8-mediated E2F1 transcription in cancer cells. Therefore, our results suggest that, in cancer, frequent and persistent expression of PAX8 is required for cell growth control through transcriptional activation of E2F1 expression and upregulation of the RB-E2F1 pathway.
authors: Department of Pathology, Dunedin School of Medicine, University of Otago, New Zealand.
authors: C G
authors: CG
authors: Li
authors: J E
authors: JE
authors: Nyman
authors: A W
authors: AW
authors: Braithwaite
authors: M R
authors: MR
authors: Eccles
references: EMBO J. 2001 May 1;20(9):2273-85
references: 11331592
references: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18562-6
references: 16352731
references: Genes Dev. 2010 Jul 1;24(13):1364-76
references: 20551165
references: J Mol Endocrinol. 1998 Dec;21(3):347-54
references: 9845675
references: Nat Cell Biol. 2001 Feb;3(2):198-203
references: 11175753
references: Mod Pathol. 2009 Sep;22(9):1218-27
references: 19525927
references: Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W128-32
references: 18453628
references: Oncogene. 2003 Mar 13;22(10):1445-60
references: 12629508
references: Nat Med. 2000 Jan;6(1):96-9
references: 10613832
references: Nature. 2003 Jul 10;424(6945):223-8
references: 12853964
references: J Am Soc Nephrol. 2007 Apr;18(4):1121-9
references: 17314325
references: Pathol Int. 2006 May;56(5):240-5
references: 16669872
references: Kidney Int. 2006 Apr;69(7):1139-45
references: 16609680
references: Oncogene. 2005 Oct 27;24(47):6993-7001
references: 16007137
references: J Invest Dermatol. 2010 May;130(5):1465-8
references: 20107488
references: Nat Rev Cancer. 2008 Sep;8(9):671-82
references: 18650841
references: Development. 1998 Aug;125(16):3063-74
references: 9671580
references: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3263-8
references: 12626766
references: J Neurosci. 1994 Mar;14(3 Pt 2):1395-412
references: 8126546
references: Gynecol Oncol. 2007 Feb;104(2):331-7
references: 17064757
references: Nat Genet. 1998 May;19(1):83-6
references: 9590296
references: Bioessays. 1997 Sep;19(9):755-65
references: 9297966
references: J Biol Chem. 1995 Sep 29;270(39):23139-42
references: 7559458
references: Br J Cancer. 1999 Mar;79(7-8):1111-20
references: 10098744
references: Nat Cell Biol. 2001 Jul;3(7):667-74
references: 11433299
references: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6914-8
references: 8346196
references: Oncogene. 2010 Apr 22;29(16):2357-67
references: 20140018
references: Cell. 1983 Dec;35(3 Pt 2):603-10
references: 6606489
references: Mod Pathol. 2006 Mar;19(3):356-63
references: 16400326
references: J Am Soc Nephrol. 2009 Oct;20(10):2112-7
references: 19713310
references: Genes Dev. 1998 Jan 1;12(1):95-106
references: 9420334
references: Mol Cell Biol. 2006 Jul;26(14):5360-72
references: 16809772
references: Cancer Res. 1996 Oct 15;56(20):4620-4
references: 8840974
references: J Cell Sci. 2004 May 1;117(Pt 11):2173-81
references: 15126619
references: Cell. 1991 Jun 14;65(6):1053-61
references: 1828392
references: Development. 1990 Oct;110(2):643-51
references: 1723950
references: Am J Pathol. 1995 Jan;146(1):40-5
references: 7856737
references: Genes Dev. 1994 Jul 1;8(13):1514-25
references: 7958836
references: Cancer Res. 2008 Jul 15;68(14):5724-32
references: 18632625
references: Genes Dev. 1998 Aug 1;12(15):2245-62
references: 9694791
references: Eur J Biochem. 1995 Mar 15;228(3):899-911
references: 7737192
references: Cell. 1995 May 5;81(3):323-30
references: 7736585
references: Oncogene. 2008 Jul 10;27(30):4172-9
references: 18345030
references: Genes Dev. 1996 Dec 1;10(23):2949-59
references: 8956996
references: J Biol Chem. 1997 Nov 28;272(48):30135-40
references: 9374493
references: Hum Pathol. 2001 Mar;32(3):282-7
references: 11274636
references: Eur J Cell Biol. 1997 Feb;72(2):159-65
references: 9157012
references: Mol Cell Biol. 1999 Mar;19(3):2051-60
references: 10022892
references: Mol Cell. 2005 Dec 9;20(5):699-708
references: 16337594
references: Mol Cell Biol. 1992 Sep;12(9):4230-41
references: 1508216
references: Biochem Biophys Res Commun. 2007 Sep 28;361(3):611-4
references: 17669361
references: Am J Surg Pathol. 2010 May;34(5):723-9
references: 20414099
references: Oncogene. 2006 Aug 28;25(38):5268-76
references: 16936747
references: Am J Pathol. 2004 Aug;165(2):397-414
references: 15277215
references: Nat Genet. 1998 May;19(1):87-90
references: 9590297
references: EMBO Rep. 2008 Mar;9(3):252-9
references: 18202719
references: Biochem J. 1998 Apr 1;331 ( Pt 1):37-40
references: 9512459
references: Curr Opin Cell Biol. 2007 Dec;19(6):697-704
references: 18035529
references: Genes Dev. 2003 May 1;17(9):1115-29
references: 12695333
references: J Clin Endocrinol Metab. 2001 Jan;86(1):234-8
references: 11232006
references: Genes Dev. 2002 Nov 15;16(22):2958-70
references: 12435636
references: Nat Protoc. 2008;3(6):1032-45
references: 18536650