title: Differential p53-independent outcomes of p19(Arf) loss in oncogenesis.
abstract: One reported function of the tumor suppressor p19(Arf) is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19(Arf), p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19(Arf) in prostate epithelium does not accelerate-but rather partially inhibits-the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19(Arf) double-mutant mice. In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19(Arf). However, in contrast to that in the prostate epithelium, p19(Arf) deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance. Consistent with the effect of p19(Arf) loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14(ARF) (the human equivalent of mouse p19(Arf)). Collectively, these data reveal differential consequences of p19(Arf) inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway.
authors.affiliation: Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
authors.forename: Nille
authors.initials: N
authors.lastname: Behrendt
authors.forename: Ainara
authors.initials: A
authors.lastname: Egia
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.forename: William
authors.initials: W
authors.lastname: Gerald
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
references.citation: Mol Cell Biol. 2007 Jan;27(2):662-77
references.pmid: 17060456
references.citation: EMBO J. 1998 Sep 1;17(17):5001-14
references.pmid: 9724636
references.citation: Lancet Oncol. 2008 May;9(5):445-52
references.pmid: 18424233
references.citation: Methods Mol Biol. 2003;222:147-66
references.pmid: 12710685
references.citation: Nature. 2005 Aug 4;436(7051):725-30
references.pmid: 16079851
references.citation: MMWR Surveill Summ. 2004 Jun 4;53(3):1-108
references.pmid: 15179359
references.citation: Nature. 2008 Oct 9;455(7214):813-7
references.pmid: 18716620
references.citation: Oncogene. 2004 Nov 11;23(53):8571-80
references.pmid: 15467756
references.citation: Front Radiat Ther Oncol. 2008;41:49-57
references.pmid: 18544985
references.citation: Mod Pathol. 2006 Oct;19(10):1339-43
references.pmid: 16799475
references.citation: Urol J. 2007 Spring;4(2):95-100
references.pmid: 17701929
references.citation: Cancer Res. 1999 May 1;59(9):2217-22
references.pmid: 10232611
references.citation: Cancer Res. 2007 Aug 1;67(15):7350-7
references.pmid: 17671205
references.citation: Nature. 1995 Nov 9;378(6553):203-6
references.pmid: 7477326
references.citation: Cancer Cell. 2004 Oct;6(4):309-11
references.pmid: 15488753
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4240-5
references.pmid: 10200246
references.citation: Cancer Res. 2008 Dec 1;68(23):9608-13
references.pmid: 19047137
references.citation: Nature. 1995 Nov 9;378(6553):206-8
references.pmid: 7477327
references.citation: Nat Rev Cancer. 2006 Sep;6(9):663-73
references.pmid: 16915296
references.citation: Exp Mol Pathol. 2006 Oct;81(2):115-22
references.pmid: 16919268
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8292-7
references.pmid: 9653180
references.citation: Nat Genet. 1998 Aug;19(4):348-55
references.pmid: 9697695
references.citation: Cell. 1997 Nov 28;91(5):649-59
references.pmid: 9393858
references.citation: Cell. 2006 Oct 20;127(2):265-75
references.pmid: 17055429
references.citation: Nat Genet. 2008 Mar;40(3):316-21
references.pmid: 18264097
references.citation: Nature. 2007 Aug 2;448(7153):595-9
references.pmid: 17671502
references.citation: J Biol Chem. 2000 Sep 1;275(35):27473-80
references.pmid: 10842176
references.citation: Neoplasia. 2008 Feb;10(2):177-88
references.pmid: 18283340
references.citation: Nat Rev Mol Cell Biol. 2001 Oct;2(10):731-7
references.pmid: 11584300
references.citation: Nature. 2006 May 25;441(7092):475-82
references.pmid: 16598206
references.citation: Nat Cell Biol. 1999 May;1(1):20-6
references.pmid: 10559859
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5246-50
references.pmid: 9560261
references.citation: Curr Opin Genet Dev. 2000 Feb;10(1):94-9
references.pmid: 10679383
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16158-63
references.pmid: 17911267