Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis - PubMed (original) (raw)
doi: 10.1038/ncb1567. Epub 2007 Apr 22.
Affiliations
- PMID: 17450133
- DOI: 10.1038/ncb1567
Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis
Christopher J Sarkisian et al. Nat Cell Biol. 2007 May.
Abstract
Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation - similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 - stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation - similar to those found in tumours bearing endogenous Kras2 mutations - induce cellular senescence that is Ink4a-Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53-Ink4a-Arf-dependent senescence checkpoints.
Comment in
- Barriers to Ras transformation.
Ferbeyre G. Ferbeyre G. Nat Cell Biol. 2007 May;9(5):483-5. doi: 10.1038/ncb0507-483. Nat Cell Biol. 2007. PMID: 17473855 No abstract available.
Similar articles
- Oncogene-induced senescence as an initial barrier in lymphoma development.
Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dörken B, Jenuwein T, Schmitt CA. Braig M, et al. Nature. 2005 Aug 4;436(7051):660-5. doi: 10.1038/nature03841. Nature. 2005. PMID: 16079837 - Transcriptional factor HBP1 targets P16(INK4A), upregulating its expression and consequently is involved in Ras-induced premature senescence.
Li H, Wang W, Liu X, Paulson KE, Yee AS, Zhang X. Li H, et al. Oncogene. 2010 Sep 9;29(36):5083-94. doi: 10.1038/onc.2010.252. Epub 2010 Jun 28. Oncogene. 2010. PMID: 20581871 - p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis.
Cabodi S, Tinnirello A, Di Stefano P, Bisarò B, Ambrosino E, Castellano I, Sapino A, Arisio R, Cavallo F, Forni G, Glukhova M, Silengo L, Altruda F, Turco E, Tarone G, Defilippi P. Cabodi S, et al. Cancer Res. 2006 May 1;66(9):4672-80. doi: 10.1158/0008-5472.CAN-05-2909. Cancer Res. 2006. PMID: 16651418 - WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis.
Li M, Lewis B, Capuco AV, Laucirica R, Furth PA. Li M, et al. Oncogene. 2000 Feb 21;19(8):1010-9. doi: 10.1038/sj.onc.1203271. Oncogene. 2000. PMID: 10713684 Review. - Molecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging.
Zhang H. Zhang H. J Cell Physiol. 2007 Mar;210(3):567-74. doi: 10.1002/jcp.20919. J Cell Physiol. 2007. PMID: 17133363 Review.
Cited by
- Conditional expression of oncogenic C-RAF in mouse pulmonary epithelial cells reveals differential tumorigenesis and induction of autophagy leading to tumor regression.
Ceteci F, Xu J, Ceteci S, Zanucco E, Thakur C, Rapp UR. Ceteci F, et al. Neoplasia. 2011 Nov;13(11):1005-18. doi: 10.1593/neo.11652. Neoplasia. 2011. PMID: 22131876 Free PMC article. - N terminus of ASPP2 binds to Ras and enhances Ras/Raf/MEK/ERK activation to promote oncogene-induced senescence.
Wang Z, Liu Y, Takahashi M, Van Hook K, Kampa-Schittenhelm KM, Sheppard BC, Sears RC, Stork PJ, Lopez CD. Wang Z, et al. Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):312-7. doi: 10.1073/pnas.1201514110. Epub 2012 Dec 17. Proc Natl Acad Sci U S A. 2013. PMID: 23248303 Free PMC article. - Mesenchymal tumor cells drive adaptive resistance of Trp53-/- breast tumor cells to inactivated mutant Kras.
van Weele LJ, Djomehri SI, Cai S, Antony J, Sikandar SS, Qian D, Ho WHD, West RB, Scheeren FA, Clarke MF. van Weele LJ, et al. Mol Oncol. 2022 Sep;16(17):3128-3145. doi: 10.1002/1878-0261.13220. Epub 2022 Apr 23. Mol Oncol. 2022. PMID: 35398967 Free PMC article. - Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes.
Teh MT, Gemenetzidis E, Chaplin T, Young BD, Philpott MP. Teh MT, et al. Mol Cancer. 2010 Feb 26;9:45. doi: 10.1186/1476-4598-9-45. Mol Cancer. 2010. PMID: 20187950 Free PMC article. - Irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation.
Afifi MM, Crncec A, Cornwell JA, Cataisson C, Paul D, Ghorab LM, Hernandez MO, Wong M, Kedei N, Cappell SD. Afifi MM, et al. Cell Rep. 2023 Sep 26;42(9):113079. doi: 10.1016/j.celrep.2023.113079. Epub 2023 Aug 31. Cell Rep. 2023. PMID: 37656618 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous