Wierstra Inken, Alves Jürgen
Institute of Molecular Biology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Biol Chem. 2006 Jul;387(7):949-62. doi: 10.1515/BC.2006.119.
The proliferation-stimulating transactivator FOXM1c (MPP2) is repressed by RB and activated by cyclin D1/Cdk4 and therefore behaves like E2F. Despite its strong transactivation domain, FOXM1c is kept almost inactive by two different inhibitory domains, the N-terminus and the central domain. The tumor suppressor RB binds directly to the central domain of FOXM1c and thereby indirectly represses the transactivation domain, so that the central domain of FOXM1c functions as an RB-recruiting negative-regulatory domain. Cyclin D1/Cdk4 releases FOXM1c from this repression by RB and from the repression by its own inhibitory N-terminus, thereby strongly activating FOXM1c. However, cyclin D1/Cdk4 does not directly affect the transactivation domain or the DNA-binding domain. By phosphorylation of RB, but not FOXM1c, cyclin D1/Cdk4 interrupts their direct interaction and thus abrogates the repression of FOXM1c by RB. Cyclin D1/Cdk4 also eliminates the inhibition of the transactivation domain by the N-terminus of FOXM1c, probably by interruption of their direct interaction. Consequently, the G1-phase proliferation signal cyclin D1/Cdk4 converts FOXM1c from an almost inactive form into a strong transactivator in G1-phase, i.e., just at the time point at which the transcriptional activity of FOXM1 is required for stimulation of the G1/S-transition.
增殖刺激反式激活因子FOXM1c（MPP2）受RB抑制，受细胞周期蛋白D1/Cdk4激活，因此其行为类似于E2F。尽管FOXM1c具有强大的反式激活结构域，但它通过两个不同的抑制结构域（N端和中央结构域）几乎保持无活性状态。肿瘤抑制因子RB直接与FOXM1c的中央结构域结合，从而间接抑制反式激活结构域，使得FOXM1c的中央结构域发挥RB招募负调控结构域的作用。细胞周期蛋白D1/Cdk4使FOXM1c从RB的这种抑制以及其自身抑制性N端的抑制中释放出来，从而强烈激活FOXM1c。然而，细胞周期蛋白D1/Cdk4并不直接影响反式激活结构域或DNA结合结构域。通过磷酸化RB而非FOXM1c，细胞周期蛋白D1/Cdk4中断它们之间的直接相互作用，从而消除RB对FOXM1c的抑制。细胞周期蛋白D1/Cdk4还可能通过中断FOXM1c N端与反式激活结构域之间的直接相互作用，消除N端对反式激活结构域的抑制。因此，G1期增殖信号细胞周期蛋白D1/Cdk4在G1期将FOXM1c从几乎无活性的形式转变为强大的反式激活因子，即在刺激G1/S转换需要FOXM1转录活性的时间点。
