title: CSF1 is a novel p53 target gene whose protein product functions in a feed-forward manner to suppress apoptosis and enhance p53-mediated growth arrest.
abstract: The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. We previously reported that the proline 72 polymorphic variant of p53 (P72) demonstrates increased ability to transactivate a subset of genes, relative to arginine 72 (R72); one of these genes is macrophage colony stimulating factor (CSF1). At present, the mechanism(s) underlying the increased transcriptional activity of P72 toward genes like CSF1 have not been completely elucidated. Additionally, the consequences of increased transcription of genes like CSF1 by the P72 variant to the downstream p53 pathway are unknown. In this report, we address these issues. We show that the CSF1 gene contains a conserved binding site for p53, and interestingly that the P72 variant shows increased ability to bind to this site. Moreover, we show that increased CSF1/CSF1R signaling in P72 cells feeds back on the p53 pathway to enhance p53 phosphorylation, levels, and transactivation of target genes, particularly the cyclin-dependent kinase inhibitor p21 (CDKN1A). This leads to an increase in p53-mediated growth arrest, along with a concomitant decrease in apoptosis. Notably, the CSF1/CSF1R signaling axis is overexpressed in several epithelial cancers, and there is clinical evidence that this pathway plays a role in radio-resistance of some cancers. We show that cells expressing CSF1 and CSF1R are indeed radio-resistant, and further, that this effect requires p53. These combined data are the first to implicate the CSF1/CSF1R pathway in the decision between p53-mediated growth arrest and apoptosis. They are also the first to highlight a cytokine as influential in cell fate determined by p53 in epithelial cells. Finally, these data may explain the association of the P72 variant and the CSF1/CSF1R pathway with increased senescence and radio-resistance in some epithelial tumor types.
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Azzam
authors.forename: Xuting
authors.initials: X
authors.lastname: Wang
authors.forename: Douglas
authors.initials: D
authors.lastname: Bell
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D016158:Genes, p53; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D051379:Mice; D011392:Proline / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D001120:Arginine; D011392:Proline
references.citation: Int J Radiat Oncol Biol Phys. 1999 Nov 1;45(4):969-73
references.pmid: 10571204
references.citation: Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):173-7
references.pmid: 14734466
references.citation: Biochim Biophys Acta. 1996 Jun 7;1287(2-3):77-102
references.pmid: 8672531
references.citation: Oncogene. 2008 Oct 27;27(50):6507-21
references.pmid: 18955976
references.citation: Mech Ageing Dev. 2008 Apr;129(4):175-82
references.pmid: 18272203
references.citation: Pathol Oncol Res. 2010 Dec;16(4):563-8
references.pmid: 20309662
references.citation: Mol Cell. 2006 Dec 28;24(6):841-51
references.pmid: 17189187
references.citation: Blood. 1995 May 15;85(10):2691-8
references.pmid: 7742528
references.citation: Clin Cancer Res. 1998 Aug;4(8):1851-6
references.pmid: 9717811
references.citation: Clin Cancer Res. 1997 Jun;3(6):999-1007
references.pmid: 9815777
references.citation: Nucleic Acids Res. 2011 Jan;39(1):178-89
references.pmid: 20817676
references.citation: Oncogene. 2001 Jan 18;20(3):320-8
references.pmid: 11313961
references.citation: Nat Genet. 2003 Mar;33(3):357-65
references.pmid: 12567188
references.citation: Cell Cycle. 2005 Sep;4(9):1264-71
references.pmid: 16082224
references.citation: J Gastroenterol. 2007 Jun;42(6):456-60
references.pmid: 17671760
references.citation: Hum Mol Genet. 2007 May 15;16(10):1188-200
references.pmid: 17409198
references.citation: Cancer Res. 2001 Nov 15;61(22):8158-63
references.pmid: 11719445
references.citation: Mol Cell. 2006 Dec 28;24(6):827-39
references.pmid: 17189186
references.citation: PLoS One. 2011 Mar 04;6(3):e17574
references.pmid: 21394211
references.citation: PLoS One. 2011 Jan 20;6(1):e15813
references.pmid: 21283750
references.citation: Nat Rev Genet. 2004 Apr;5(4):276-87
references.pmid: 15131651
references.citation: Mol Cell Biol. 2011 Mar;31(6):1201-13
references.pmid: 21245379
references.citation: Mol Reprod Dev. 1997 Jan;46(1):71-4
references.pmid: 8981366
references.citation: Curr Opin Immunol. 2006 Feb;18(1):39-48
references.pmid: 16337366
references.citation: Science. 1998 Nov 20;282(5393):1497-501
references.pmid: 9822382
references.citation: Hum Hered. 1994 Sep-Oct;44(5):266-70
references.pmid: 7927355
references.citation: Genes Dev. 1996 Oct 1;10(19):2438-51
references.pmid: 8843196
references.citation: Oncogene. 2004 Apr 22;23(19):3328-37
references.pmid: 15077186
references.citation: Carcinogenesis. 2005 Oct;26(10):1829-34
references.pmid: 15917304
references.citation: Cell Cycle. 2011 May 1;10(9):1352-5
references.pmid: 21566457
references.citation: Int J Colorectal Dis. 2011 Feb;26(2):235-8
references.pmid: 20669023
references.citation: EMBO J. 1997 Mar 17;16(6):1391-400
references.pmid: 9135154
references.citation: FASEB J. 2010 May;24(5):1347-53
references.pmid: 20019240
references.citation: Oncogene. 1996 Dec 19;13(12):2575-87
references.pmid: 9000131
references.citation: Cell Death Differ. 2006 Jun;13(6):994-1002
references.pmid: 16543937
references.citation: Neoplasia. 2012 Jul;14(7):634-43
references.pmid: 22904680
references.citation: Genes Dev. 1995 Mar 1;9(5):600-11
references.pmid: 7698649
references.citation: Nat Rev Cancer. 2009 Feb;9(2):95-107
references.pmid: 19165225
references.citation: Diabetes. 2008 Nov;57(11):3136-44
references.pmid: 18678618
references.citation: Cancer Res. 2005 Apr 1;65(7):2583-7
references.pmid: 15805253
references.citation: Oncogene. 2006 Mar 13;25(11):1602-11
references.pmid: 16550160
references.citation: Cancer Res. 2010 Jul 15;70(14):5851-9
references.pmid: 20587514
references.citation: Nature. 2007 Feb 8;445(7128):656-60
references.pmid: 17251933
references.citation: Am J Hum Genet. 1999 Dec;65(6):1782-5
references.pmid: 10577935
references.citation: Nat Methods. 2008 Sep;5(9):829-34
references.pmid: 19160518