Abstract
Senescence is recently characterized as one of the evolutionarily conserved protective mechanisms against tumor development. Several upstream factors including oxidative stress, DNA damage and overexpression of certain oncoproteins have been shown to induce premature senescence. Interestingly, it has been discovered that instead of promoting tumorigenesis, loss of certain tumor suppressors such as TSC2, PTEN and NF1 induce premature senescence under certain conditions, presumably by activating the downstream oncoproteins mTORC1/S6k, Akt and Ras, respectively. Interestingly, it has been observed by multiple groups that acute loss of Cdh1 also leads to premature senescence in several cellular settings including mouse embryonic fibroblasts and human primary fibroblasts. This is in part due to the fact that Cdh1 loss leads to stabilization of Ets2, which increases p16 expression and causes premature senescence. Moreover, recent studies from our laboratory further suggested that loss of Cdh1 results in the activation of both the Claspin/Chk1/p53 and the Rb/E2F1 pathways, which ultimately leads to premature senescence in primary human fibroblasts but not in transformed cells with defective p53/Rb pathways. Therefore, our studies support the idea that onset of premature senescence serves as a protection mechanism against sporadic tumorigenesis. It also indicates that loss of Cdh1 tumor suppressor is a relatively late event, which only benefits tumorigenesis for late stage tumors with defective Rb and p53 tumor suppressor pathways. More importantly, our results also indicate that Cdh1 could be an anti-cancer target in certain settings, as complete inactivation of Cdh1 in early stage tumors with wild-type p53 and Rb pathways will lead to induction of premature senescence, thereby aiding tumor regression.
These authors contributed equally to this work
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Bloom J, Cross FR (2007) Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol Cell Biol 8:149–160
Campisi J (1996) Replicative senescence: an old lives’ tale? Cell 84:497–500
Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740
Cao L, Li W, Kim S, Brodie SG, Deng CX (2003) Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform. Genes Dev 17:201–213
Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z (2006) A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38:1043–1048
Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K (2006) A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10:459–472
Dial JM, Petrotchenko EV, Borchers CH (2007) Inhibition of APCCdh1 activity by Cdh1/Acm1/Bmh1 ternary complex formation. J Biol Chem 282:5237–5248
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367
Doree M, Galas S (1994) The cyclin-dependent protein kinases and the control of cell division. FASEB J 8:1114–1121
Frescas D, Pagano M (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8:438–449
Gao D, Inuzuka H, Korenjak M, Tseng A, Wu T, Wan L, Kirschner M, Dyson N, Wei W (2009a) Cdh1 regulates cell cycle through modulating the claspin/Chk1 and the Rb/E2F1 pathways. Mol Biol Cell 20:3305–3316
Gao D, Inuzuka H, Tseng A, Chin RY, Toker A, Wei W (2009b) Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. Nat Cell Biol 11:397–408
Garcia-Higuera I, Manchado E, Dubus P, Canamero M, Mendez J, Moreno S, Malumbres M (2008) Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nat Cell Biol 10:802–811
Hsu JY, Reimann JD, Sorensen CS, Lukas J, Jackson PK (2002) E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat Cell Biol 4:358–366
Hwang ES, Yoon G, Kang HT (2009) A comparative analysis of the cell biology of senescence and aging. Cell Mol Life Sci 66:2503–2524
Kraft C, Vodermaier HC, Maurer-Stroh S, Eisenhaber F, Peters JM (2005) The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates. Mol Cell 18:543–553
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479
Li M, Shin YH, Hou L, Huang X, Wei Z, Klann E, Zhang P (2008) The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory. Nat Cell Biol 10:1083–1089
Listovsky T, Oren YS, Yudkovsky Y, Mahbubani HM, Weiss AM, Lebendiker M, Brandeis M (2004) Mammalian Cdh1/Fzr mediates its own degradation. EMBO J 23:1619–1626
Lukas C, Sorensen CS, Kramer E, Santoni-Rugiu E, Lindeneg C, Peters JM, Bartek J, Lukas J (1999) Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature 401:815–818
Mallette FA, Gaumont-Leclerc MF, Ferbeyre G (2007) The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev 21:43–48
Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E (2001) Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409:1067–1070
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
Shaik S, Liu P, Fukushima H, Wang Z, Wei W (2012) Protein degradation in cell cycle. In: Yixian Zheng (ed) eLS. Wiley, Chichester, pp 1–8
Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14:289–300
Sitte N, Merker K, von Zglinicki T, Grune T (2000) Protein oxidation and degradation during proliferative senescence of human MRC-5 fibroblasts. Free Radic Biol Med 28:701–708
Song MS, Carracedo A, Salmena L, Song SJ, Egia A, Malumbres M, Pandolfi PP (2011) Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell 144:187–199
Sudo T, Ota Y, Kotani S, Nakao M, Takami Y, Takeda S, Saya H (2001) Activation of Cdh1-dependent APC is required for G1 cell cycle arrest and DNA damage-induced G2 checkpoint in vertebrate cells. EMBO J 20:6499–6508
Vodermaier HC (2004) APC/C and SCF: controlling each other and the cell cycle. Curr Biol 14:R787–R796
Wan L, Zou W, Gao D, Inuzuka H, Fukushima H, Berg AH, Drapp R, Shaik S, Hu D, Lester C, Eguren M, Malumbres M, Glimcher LH, Wei W (2011) Cdh1 regulates osteoblast function through an APC/C-independent modulation of Smurf1. Mol Cell 44:721–733
Wang CX, Fisk BC, Wadehra M, Su H, Braun J (2000) Overexpression of murine fizzy-related (fzr) increases natural killer cell-mediated cell death and suppresses tumor growth. Blood 96:259–263
Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr (2004) Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428:194–198
Young AP, Schlisio S, Minamishima YA, Zhang Q, Li L, Grisanzio C, Signoretti S, Kaelin WG Jr (2008) VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol 10:361–369
Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL, Kwiatkowski DJ (2003) Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 112:1223–1233
Zhou Y, Ching YP, Chun AC, Jin DY (2003) Nuclear localization of the cell cycle regulator CDH1 and its regulation by phosphorylation. J Biol Chem 278:12530–12536
Acknowledgements
This work was supported in part from the grants (GM089763 and GM094777) from National Institutes of Health to Wenyi Wei. Shavali Shaik, Pengda Liu and Zhiwei Wang were supported by the institutional NRSA T-32 training grant.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Shaik, S., Liu, P., Wang, Z., Wei, W. (2014). Loss of Cdh1 Triggers Premature Senescence in Part via Activation of Both the RB/E2F1 and the CLASPIN/CHK1/P53 Tumor Suppressor Pathways. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 2. Tumor Dormancy and Cellular Quiescence and Senescence, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7726-2_20
Download citation
DOI: https://doi.org/10.1007/978-94-007-7726-2_20
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-7725-5
Online ISBN: 978-94-007-7726-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)