Hara E, Hall M, Peters G
Imperial Cancer Research Fund Laboratories, London, UK.
EMBO J. 1997 Jan 15;16(2):332-42. doi: 10.1093/emboj/16.2.332.
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.
螺旋-环-螺旋（HLH）蛋白Id2被认为通过负向调节碱性螺旋-环-螺旋（bHLH）转录因子的功能来影响细胞生长与分化之间的平衡。Id2通过形成无法结合特定（E盒）DNA序列的异二聚体来发挥作用。在此我们表明，细胞周期蛋白依赖性激酶（Cdks）共有靶位点内丝氨酸残基的磷酸化可克服这种活性。在体外，Id2可被细胞周期蛋白E-Cdk2或细胞周期蛋白A-Cdk2磷酸化，但不能被细胞周期蛋白D依赖性激酶磷酸化。在血清刺激的人二倍体成纤维细胞中，类似的磷酸化发生在G1晚期，这与活性细胞周期蛋白E-Cdk2的出现时间一致。这些细胞中Id2的磷酸化与一种独特的依赖E盒的DNA结合复合物的恢复相关，这表明该复合物的水平受Id2的丰度和磷酸化状态的调节。这些数据在细胞周期蛋白依赖性激酶和bHLH转录因子之间建立了联系，这可能对细胞增殖和分化的调节至关重要。
