Peschiaroli Angelo, Figliola Rocco, Coltella Luana, Strom Alessandra, Valentini Alessandra, D'Agnano Igea, Maione Rossella
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università di Roma La Sapienza, Viale Regina Elena 324, 00161 Roma, Italy.
Oncogene. 2002 Nov 21;21(53):8114-27. doi: 10.1038/sj.onc.1206010.
During differentiation of skeletal myoblasts, MyoD promotes growth arrest through the induction of the cdk inhibitor p21 and the accumulation of hypophosphorylated RB protein. Myoblasts lacking RB function fail to accomplish full differentiation and undergo apoptosis. Here we show that exogenous MyoD induces apoptosis in several cell backgrounds sharing RB inactivation. This process is associated with increased levels of cell cycle-driving proteins and aberrant cell cycle progression. The inability of MyoD to induce apoptosis in a p21-null background, highlights a requirement of p21 in RB-regulated apoptosis during myogenesis. This pro-apoptotic function of p21 cannot be exerted by simple p21 over-expression, but requires the co-operation of MyoD. We also suggest that the essential aspect of p21 activity involved in such a process is related to its ability to induce the nuclear accumulation and aberrant activity of cyclin/cdk complexes. These results establish a novel link between MyoD, p21 and RB during myogenesis, providing new insights into the antagonism between muscle differentiation and loss of RB function.
在骨骼肌成肌细胞分化过程中，MyoD 通过诱导细胞周期蛋白依赖性激酶抑制剂 p21 和低磷酸化 RB 蛋白的积累来促进生长停滞。缺乏 RB 功能的成肌细胞无法完成完全分化并发生凋亡。在此我们表明，外源性 MyoD 在几种共享 RB 失活的细胞背景中诱导凋亡。这一过程与细胞周期驱动蛋白水平的增加和异常的细胞周期进程相关。MyoD 在 p21 基因缺失背景下无法诱导凋亡，这突出了 p21 在成肌过程中 RB 调节的凋亡中的必要性。p21 的这种促凋亡功能不能通过简单的 p21 过表达来发挥，而是需要 MyoD 的协同作用。我们还表明，参与这一过程的 p21 活性的关键方面与其诱导细胞周期蛋白/细胞周期蛋白依赖性激酶复合物的核积累和异常活性的能力有关。这些结果在成肌过程中建立了 MyoD、p21 和 RB 之间的新联系，为肌肉分化与 RB 功能丧失之间的拮抗作用提供了新的见解。
