Loss of Cdh1 Triggers Premature Senescence in Part via Activation of Both the RB/E2F1 and the CLASPIN/CHK1/P53 Tumor Suppressor Pathways

  • Shavali Shaik
  • Pengda Liu
  • Zhiwei Wang
  • Wenyi Wei
Part of the Tumor Dormancy and Cellular Quiescence and Senescence book series (DOQU, volume 2)


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.


Anaphase-promoting complex (APC/C) Cyclin-dependent protein kinases (Cdks) DNA binding activity of p53 DNA damage Expression of PTEN Mouse embryonic fibroblasts (MEFs) Regulation of Cdh1 Skp1-Cullin1-F-box complex (SCF) Ubiquitin proteasome system (UPS) 



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.


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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Shavali Shaik
    • 1
  • Pengda Liu
    • 1
  • Zhiwei Wang
    • 1
  • Wenyi Wei
    • 1
  1. 1.Department of Pathology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

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