Suppression of human tumor cell proliferation by Smurf2-induced senescence.
The limitation of proliferative potential in human somatic cells imposed by replicative senescence has been proposed as a mechanism of tumor suppression. The E3 ubiquitin ligase Smurf2 is up-regulated during replicative senescence in response to telomere shortening, and induces senescence when expressed adventitiously in early passage or telomerase-immortalized human fibroblasts. To investigate the generality of Smurf2's control of cell proliferation, we have studied the effects of Smurf2 up-regulation on cell proliferation in early passage human mammary epithelial cells which normally do not show elevated expression of Smurf2 during senescence, and in 16 human cancer cell lines derived from both sarcomas and carcinomas. Here we report that Smurf2 up-regulation induced senescence in a wide variety of human cell types, including highly neoplastic cell lines. Consistent with our previous findings, the ability of Smurf2 to arrest cell proliferation did not require its ubiquitin ligase activity. Furthermore, expression of the cyclin-dependent kinase inhibitor p21 was increased in tumor cells undergoing Smurf2-induced senescence, and such increase occurred independently of the transactivation function of p53. Our results, which reveal a previously unsuspected tumor suppression function for Smurf2-induced senescence, suggest that modulation of Smurf2 action may be a useful strategy for inhibition of cancer cell growth.
Zhang
Hong
H
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. hong.zhang@umassmed.edu
Teng
Yuchin
Y
Kong
Yahui
Y
Kowalski
Paul E
PE
Cohen
Stanley N
SN
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases