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Mol Cell Biol, April 1998, p. 2371-2381, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Coupling of Cell Growth Control and Apoptosis Functions of Id Proteins

John D. Norton* and Graham T. Atherton

CRC Department of Gene Regulation, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 9BX, United Kingdom

Received 22 May 1997/Returned for modification 27 July 1997/Accepted 23 December 1997

The Id family of helix-loop-helix proteins function as negative regulators of cell differentiation and as positive regulators of G1 cell cycle control. We report here that enforced overexpression of the Id3 gene suppresses the colony-forming efficiency of primary rat embryo fibroblasts. Cotransfection with the antiapoptotic Bcl2 or BclXL gene alleviates this suppression and leads to cell immortalization. Consistent with this, enforced expression of Id genes in isolation was found to be a strong inducer of apoptosis in serum-deprived fibroblast cells. Id3-induced apoptosis was mediated at least in part through p53-independent mechanisms and could be efficiently rescued by Bcl2, BclXL, and the basic helix-loop-helix protein E47, which is known to oppose the functions of Id3 in vivo through the formation of stable heterodimers. Enforced overexpression of Id proteins has previously been shown to promote the cell cycle S phase in serum-deprived embryo fibroblasts (R. W. Deed, E. Hara, G. Atherton, G. Peters, and J. D. Norton, Mol. Cell. Biol. 17:6815-6821, 1997). The extent of apoptosis induced by loss- and gain-of-function Id3 mutants and by wild-type Id3 either alone or in combination with the Bcl2, BclXL, and E47 genes was invariably correlated with the relative magnitude of cell cycle S phase promotion. In addition, Id3-transfected cell populations displaying apoptosis and those in S phase were largely coincident in different experiments. These findings highlight the close coupling between the G1 progression and apoptosis functions of Id proteins and hint at a common mechanism for this family of transcriptional regulators in cell determination.

* Corresponding author. Mailing address: CRC Department of Gene Regulation, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Rd., Manchester M20 9BX, United Kingdom. Phone: 44 161 4463129. Fax: 44 161 4463109. E-mail: grgjdn{at}picr.cr.man.ac.uk.




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