Coupling of cell growth control and apoptosis functions of Id proteins.
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.
Norton
J D
JD
CRC Department of Gene Regulation, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom. grgjdn@picr.cr.man.ac.uk
Atherton
G T
GT
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle; D002455:Cell Division / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D051379:Mice; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat; D016895:Culture Media, Serum-Free; C497453:ID1 protein, human; C497454:ID1 protein, rat; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D014157:Transcription Factors; D051020:bcl-X Protein; C075640:ID3 protein, human