The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9437445 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5403 (Electronic) Linking ISSN: 13509047 NLM ISO Abbreviation: Cell Death Differ Subsets: MEDLINE

Publication: <2003->: London : Nature Publishing Group
Original Publication: London : Edward Arnold, c1994-

DNA Damage*; Carcinogenesis/*genetics ; Neoplasms/*genetics ; Tumor Suppressor Protein p14ARF/*genetics; Amino Acid Sequence ; Animals ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Gene Expression ; Heterografts ; Humans ; Immunohistochemistry ; Mice ; Molecular Sequence Data ; Neoplasms/metabolism ; Neoplasms/pathology ; Oncogenes ; Transfection ; Tumor Suppressor Protein p14ARF/metabolism

Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16(INK4A), a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

Comment in: Cell Death Differ. 2013 Nov;20(11):1442-3. (PMID: 24096933)

Cancer Cell. 2008 Dec 9;14(6):447-57. (PMID: 19061836)
Nature. 2005 Apr 14;434(7035):864-70. (PMID: 15829956)
Nature. 2006 Nov 30;444(7119):633-7. (PMID: 17136093)
Int J Cancer. 2006 Oct 1;119(7):1513-8. (PMID: 16557569)
Cancer Biol Ther. 2009 Jul;8(14):1313-7. (PMID: 19502780)
Nature. 2005 Apr 14;434(7035):907-13. (PMID: 15829965)
J Clin Invest. 2007 Feb;117(2):314-25. (PMID: 17256055)
Wiley Interdiscip Rev Dev Biol. 2012 Sep-Oct;1(5):731-41. (PMID: 22960768)
Expert Rev Anticancer Ther. 2009 Sep;9(9):1251-60. (PMID: 19761429)
Mol Cell. 2012 Mar 30;45(6):710-8. (PMID: 22464441)
Cell Cycle. 2007 Nov 1;6(21):2697-705. (PMID: 17912037)
Mol Carcinog. 2010 Jan;49(1):94-103. (PMID: 19777566)
Nature. 2001 Feb 22;409(6823):1067-70. (PMID: 11234019)
Nature. 2006 Nov 30;444(7119):638-42. (PMID: 17136094)
Biochim Biophys Acta. 2002 Mar 14;1602(1):73-87. (PMID: 11960696)
Cancer Res. 2012 Dec 1;72(23):6279-89. (PMID: 23204322)
EMBO J. 1998 Sep 1;17(17):5001-14. (PMID: 9724636)
J Biol Chem. 2001 Nov 16;276(46):42851-6. (PMID: 11551910)
Oncogene. 1997 Jul 10;15(2):203-11. (PMID: 9244355)
Cancer Res. 2000 Jul 15;60(14):3862-71. (PMID: 10919661)
Nat Rev Mol Cell Biol. 2010 Mar;11(3):220-8. (PMID: 20177397)
J Cell Physiol. 2002 Oct;193(1):19-25. (PMID: 12209876)
Cell Cycle. 2005 May;4(5):643-5. (PMID: 15846097)
N Engl J Med. 1990 Nov 1;323(18):1228-33. (PMID: 2215606)
Oncogene. 2007 Jun 28;26(30):4329-35. (PMID: 17237816)
Nat Protoc. 2007;2(3):541-6. (PMID: 17406617)
Nat Genet. 2003 Mar;33(3):416-21. (PMID: 12590261)
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3993-8. (PMID: 10097151)
Nat Rev Mol Cell Biol. 2010 Mar;11(3):208-19. (PMID: 20177396)
Mol Cell Biol. 1998 Nov;18(11):6457-73. (PMID: 9774662)
Cell Cycle. 2003 Mar-Apr;2(2):113-5. (PMID: 12695659)
Nature. 2009 Oct 22;461(7267):1071-8. (PMID: 19847258)
Genes Cells. 2003 Feb;8(2):131-44. (PMID: 12581156)
Curr Opin Cell Biol. 2010 Dec;22(6):816-27. (PMID: 20807678)
Nat Genet. 2004 Apr;36(4):343-50. (PMID: 14991053)
PLoS One. 2008 Mar 26;3(3):e1864. (PMID: 18365017)
Carcinogenesis. 2006 Jun;27(6):1160-8. (PMID: 16537562)
Nat Rev Cancer. 2010 Jan;10(1):51-7. (PMID: 20029423)
Cancer Res. 2007 Nov 15;67(22):10899-909. (PMID: 18006835)
Nat Med. 2006 Apr;12(4):446-51. (PMID: 16565722)
Nature. 2001 Mar 1;410(6824):37-40. (PMID: 11242034)
Cell Cycle. 2003 Mar-Apr;2(2):127-33. (PMID: 12695664)
Cancer Res. 2006 Feb 15;66(4):2116-28. (PMID: 16489012)
Eur J Cancer. 2005 Nov;41(16):2403-14. (PMID: 16213134)
Cell. 2006 Oct 20;127(2):265-75. (PMID: 17055429)
Science. 2008 Mar 7;319(5868):1352-5. (PMID: 18323444)
Nat Struct Mol Biol. 2012 Jan 05;19(1):5-7. (PMID: 22218289)
Science. 1999 Apr 30;284(5415):770-6. (PMID: 10221902)
Nat Cell Biol. 2007 May;9(5):493-505. (PMID: 17450133)
Nucleic Acids Res. 2007;35(6):2093-104. (PMID: 17344317)
Mol Carcinog. 2000 Jul;28(3):139-47. (PMID: 10942530)
Cancer Res. 2004 Dec 15;64(24):9027-34. (PMID: 15604268)
J Clin Invest. 2004 Nov;114(9):1299-307. (PMID: 15520862)
Nature. 2001 May 17;411(6835):366-74. (PMID: 11357144)
Nature. 1998 Sep 10;395(6698):124-5. (PMID: 9744267)
Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a001883. (PMID: 20066118)
Nat Rev Mol Cell Biol. 2006 Sep;7(9):667-77. (PMID: 16921403)
Nature. 2013 Feb 28;494(7438):492-496. (PMID: 23446422)
Curr Opin Genet Dev. 2000 Feb;10(1):94-9. (PMID: 10679383)
J Skin Cancer. 2011;2011:210813. (PMID: 21234325)

P01 CA165980 United States CA NCI NIH HHS

0 (DNA-Binding Proteins)
0 (Tumor Suppressor Protein p14ARF)

Date Created: 20130716 Date Completed: 20140703 Latest Revision: 20211021

20240829

PMC3792440

10.1038/cdd.2013.76

23852374