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Carcinogenesis Advance Access originally published online on May 18, 2009
Carcinogenesis 2009 30(7):1252-1259; doi:10.1093/carcin/bgp115
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sequestration of E12/E47 and suppression of p27KIP1 play a role in Id2-induced proliferation and tumorigenesis

Valerie A. Trabosh, Kyle A. Divito, Baltazar D. Aguda1, Cynthia M. Simbulan-Rosenthal and Dean S. Rosenthal*

Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington, DC 20007, USA
1 Mathematical Biosciences Institute, Ohio State University, Columbus, OH 43210, USA

* To whom correspondence should be addressed. Tel: +1 202 687 1056; Fax: +1 202 687 4632; Email: rosenthd{at}georgetown.edu

Id2 is a member of the helix-loop-helix (HLH) family of transcription regulators known to antagonize basic HLH transcription factors and proteins of the retinoblastoma tumor suppressor family and is implicated in the regulation of proliferation, differentiation, apoptosis and carcinogenesis. To investigate its proposed role in tumorigenesis, Id2 or deletion mutants were re-expressed in Id2–/– dermal fibroblasts. Ectopic expression of Id2 or mutants containing the central HLH domain increased S-phase cells, cell proliferation in low and normal serum and induced tumorigenesis when grafted or subcutaneously injected into athymic mice. Similar to their downregulation in human tumors, the expression of cyclin-dependent kinase inhibitors p27KIP1 and p15INK4b was decreased by Id2; the former by downregulation of its promoter by the Id2 HLH domain-mediated sequestration of E12/E47. Re-expression of p27KIP1 in Id2-overexpressing cells reverted the hyperproliferative and tumorigenic phenotype, implicating Id2 as an oncogene working through p27KIP1. These results tie together the previously observed misregulation of Id2 with a novel mechanism for tumorigenesis.

Abbreviations: BrdU, bromodeoxyuridine; EMSA, electrophoretic mobility shift assay; FACS, fluorescence-activated cell sorting; HLH, helix-loop-helix; Id, inhibitor of differentiation; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; Rb, retinoblastoma; RT, reverse transcription; UVB, ultraviolet B

Received February 12, 2009; revised April 25, 2009; accepted May 1, 2009.


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