Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors.
The helix-loop-helix (HLH) protein Id2 is thought to affect the balance between cell growth and differentiation by negatively regulating the function of basic-helix-loop-helix (bHLH) transcription factors. Id2 acts by forming heterodimers that are unable to bind to specific (E-box) DNA sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (Cdks). In vitro, Id2 can be phosphorylated by either cyclin E-Cdk2 or cyclin A-Cdk2 but not by cyclin D-dependent kinases. Analogous phosphorylation occurs in serum-stimulated human diploid fibroblasts at a time in late G1 consistent with the appearance of active cyclin E-Cdk2. The phosphorylation of Id2 in these cells correlates with the restoration of a distinct E-box-dependent DNA-binding complex, suggesting that the levels of this complex are modulated by both the abundance and phosphorylation status of Id2. These data provide a link between cyclin-dependent kinases and bHLH transcription factors that may be critical for the regulation of cell proliferation and differentiation.
Hara
E
E
Imperial Cancer Research Fund Laboratories, London, UK.
Hall
M
M
Peters
G
G
D016475:3T3 Cells; D017502:Adenovirus E2 Proteins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002455:Cell Division; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051379:Mice; D010449:Peptide Mapping; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D014157:Transcription Factors / Q000378:metabolism*
D017502:Adenovirus E2 Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases