Hawke Thomas J, Jiang Nan, Garry Daniel J
Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas 75390-8573, USA.
J Biol Chem. 2003 Feb 7;278(6):4015-20. doi: 10.1074/jbc.M209200200. Epub 2002 Nov 21.
Foxk1 is a forkhead/winged helix transcription factor that is restricted to myogenic progenitor cells in adult skeletal muscle. Mice lacking Foxk1 (Foxk1-/-) display growth retardation and a severe impairment in skeletal muscle regeneration following injury. Here we show that myogenic progenitor cells from Foxk1-/- mice are reduced in number and have perturbed cell cycle progression (G(0)/G(1) arrest). Molecular analysis of Foxk1-/- myogenic progenitor cells revealed increased expression of the cyclin-dependent kinase inhibitor, p21(CIP), independent of changes in other cell cycle inhibitors, including p53. Combinatorial mating of Foxk1-/- mice with p21(CIP)-/- mice, to generate double mutant progeny, resulted in a complete restoration of the growth deficit, skeletal muscle regeneration, myogenic progenitor cell number, and cell cycle progression that characterized the Foxk1-/- mice. We conclude that Foxk1 is essential for regulating cell cycle progression in the myogenic progenitor cell and that the cyclin-dependent kinase inhibitor, p21(CIP), may be a downstream target of Foxk1.
Foxk1是一种叉头框/翼状螺旋转录因子，在成年骨骼肌中仅限于肌源性祖细胞。缺乏Foxk1的小鼠（Foxk1-/-）表现出生长迟缓以及损伤后骨骼肌再生的严重受损。在此我们表明，来自Foxk1-/-小鼠的肌源性祖细胞数量减少且细胞周期进程紊乱（G(0)/G(1)期阻滞）。对Foxk1-/-肌源性祖细胞的分子分析显示，细胞周期蛋白依赖性激酶抑制剂p21(CIP)的表达增加，这与包括p53在内的其他细胞周期抑制剂的变化无关。将Foxk1-/-小鼠与p21(CIP)-/-小鼠进行组合交配以产生双突变后代，导致生长缺陷、骨骼肌再生、肌源性祖细胞数量和细胞周期进程完全恢复，这些正是Foxk1-/-小鼠的特征。我们得出结论，Foxk1对于调节肌源性祖细胞的细胞周期进程至关重要，并且细胞周期蛋白依赖性激酶抑制剂p21(CIP)可能是Foxk1的下游靶点。
