Abstract
c-Abl is a proto-oncogene that is essential for mouse development and tissue homeostasis. Misregulation of c-Abl, as seen in the constitutively active BCR-ABL, is the leading cause of human chronic myeloid leukemia. However, how the Abl proteins execute their functions still remains largely unknown. Here, we report an important role for c-Abl in replicative senescence and immortalization by regulating the expression of two tumor suppressors that induce cellular senescence, p53 and p16INK4a. Using primary mouse embryonic fibroblasts (MEFs), we show that c-Abl −/− cells were more resistant to immortalization than wildtype cells using a standard 3T3 or 3T9 protocol. We could only immortalize three out of nine c-Abl −/− MEF cultures even when we increased the number of starting cells. This resistance was attributed to premature senescence and reduced survival in senescent c-Abl −/− cells due to an increase in p16INK4a and p53 expression. Deleting p53 allows c-Abl −/− p53 −/− MEFs to bypass senescence to be spontaneously immortalized. Cell immortalization, but not senescence, was generally accompanied by mutations in p53 in both wildtype and c-Abl −/− MEFs, although the spectrum is different from that of human tumors. The role for c-Abl in regulating cell senescence and immortalization might explain some of the developmental defects in c-Abl −/− mice and how BCR-ABL transforms cells.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barlow C, Liyanage M, Moens PB, Deng CX, Ried T, Wynshaw-Boris A (1997) Partial rescue of the prophase I defects of Atm-deficient mice by p53 and p21 null alleles. Nat Genet 17:462–466
Beausejour CM, Campisi J (2006) Ageing: balancing regeneration and cancer. Nature 443:404–405
Ben-Porath I, Weinberg RA (2005) The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37:961–976
Cao C, Leng Y, Kufe D (2003) Catalase activity is regulated by c-Abl and Arg in the oxidative stress response. J Biol Chem 278:29667–29675
Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher CJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M (2005) Tumour biology: senescence in premalignant tumours. Nature 436:642
Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, Larue V, Pritchard C, Marais P (2009) Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15:294–303
Feng Z, Zhang C, Wu R, Hu W (2011) Tumor suppressor p53 meets microRNAs. J Mol Cell Biol 3:44–50
Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77:81–137
Hantschel O, Superti-Furga G (2004) Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol 5:33–44
Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460
Harvey DM, Levine AJ (1991) p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts. Genes Dev 5:2375–2385
Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636
Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621
Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311:1257
Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U (2007) Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev 128:36–44
Koleske AJ, Gifford AM, Scott ML, Nee M, Bronson RT, Miczek KA, Baltimore D (1998) Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 21:1259–1272
Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457
Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479
Leong WF, Chau JF, Li B (2009) p53 deficiency leads to compensatory up-regulation of p16INK4a. Mol Cancer Res 7:354–360
Li B (2005) c-Abl in oxidative stress, aging and cancer. Cell Cycle 4:246–248
Li B, Boast S, de los Santos K, Schieren I, Quiroz M, Teitelbaum SL, Tondravi MM, Goff SP (2000) Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat Genet 24:304–308
Li B, Wang X, Rasheed N, Hu Y, Boast S, Ishii T, Nakayama K, Nakayama KI, Goff SP (2004) Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C delta. Genes Dev 18:1824–1837
Lu T, Finkel T (2008) Free radicals and senescence. Exp Cell Res 314:1918–1922
Lundberg AS, Hahn WC, Gupta P, Weinberg RA (2000) Genes involved in senescence and immortalization. Curr Opin Cell Biol 12:705–709
Meltser V, Ben-Yehoyada M, Shaul Y (2011) c-Abl tyrosine kinase in the DNA damage response: cell death and more. Cell Death Diff 18:2–4
Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724
Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452
Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5:741–747
Pendergast AM (2002) The Abl family kinases: mechanisms of regulation and signaling. Adv Cancer Res 85:51–100
Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mut 28:622–629
Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979
Schwartzberg PL, Stall AM, Hardin JD, Bowdish KS, Humaran T, Boast S, Harbison ML, Robertson EJ, Goff SP (1991) Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 65:1165–1175
Serrano M, Blasco MA (2001) Putting the stress on senescence. Curr Opin Cell Biol 13:748–753
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602
Sharpless NE, DePinho RA (2004) Telomeres, stem cells, senescence, and cancer. J Clin Invest 113:160–168
Shaul Y (2000) c-Abl: activation and nuclear targets. Cell Death Diff 7:10–16
Shay JW, Pereira-Smith OM, Wright WE (1991) A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 196:33–39
Shen Z (2011) Genomic instability and cancer: an introduction. J Mol Cell Biol 3:1–3
Sherr CJ, DePinho RA (2000) Cellular senescence: mitotic clock or culture shock? Cell 102:407–410
Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC (1991) Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65:1153–1163
Van Etten RA (1999) Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol 9:179–186
Wang JY (2004) Controlling Abl: auto-inhibition and co-inhibition? Nat Cell Biol 6:3–7
Wang X, Zeng L, Wang J, Chau JF, Lai KP, Jia D, Poonepalli A, Hande MP, Liu H, He G, He L, Li B (2011) A positive role for c-Abl in Atm and Atr activation in DNA damage response. Cell Death Diff 18:5–15
Whibley C, Odell AF, Nedelko T, Balaburski G, Murphy M, Liu Z, Stevens L, Walker LH, Routledge M, Hollstein M (2010) Wild-type and Hupki (human p53 knock-in) murine embryonic fibroblasts: p53/ARF pathway disruption in spontaneous escape from senescence. J Biol Chem 285:11326–11335
Wong S, Witte ON (2004) The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 22:247–306
Wu Y, Zakian VA (2010) Identity crisis when telomeres left unprotected. J Mol Cell Biol 2:14–16
Xu Y, Baltimore D (1996) Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev 10:2401–2410
Acknowledgements
We would like to thank Ian Hang In and Terence Cheng for technical assistance. This work was supported by grants from the Ministry of Science and Technology of China (The National Key Scientific Program (2012CB966901, to B. L.) and 863 program (2011AA02A111)), the National Natural Science Foundation of China (81130039, 31071229, and 81121001), Shanghai Pujiang Program (10PJ1405000), Cheung Kong Scholars Program of the Ministry of Education, and Agency for Science, Technology and Research of Singapore.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Man Zhang and Lili Li contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(PDF 99 kb)
About this article
Cite this article
Zhang, M., Li, L., Wang, Z. et al. A role for c-Abl in cell senescence and spontaneous immortalization. AGE 35, 1251–1262 (2013). https://doi.org/10.1007/s11357-012-9452-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-012-9452-4