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Carcinogenesis Advance Access published online on May 18, 2009
Carcinogenesis, 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 plays a role in Id2-induced proliferation and tumorigenesis

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

Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20007
* Ohio State University, Mathematical Biosciences Institute, Columbus, OH 43210

Address correspondence to: Dean S. Rosenthal, Ph.D., Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, 3900 Reservoir Road NW, Washington, DC 20007, USA. Tel.: (202) 687-1056. Fax: (202) 687-4632. E-mail: 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 (Rb) 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 helix-loop helix (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 were 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.

Key Words: cell cycle • HLH • fibrosarcoma • dermal fibroblasts • skin graft

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


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