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Mol Cell Biol, April 1998, p. 2371-2381, Vol. 18, No. 4
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.
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
*
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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