Absence of p21CIP rescues myogenic progenitor cell proliferative and regenerative capacity in Foxk1 null mice
Absence of p21CIP rescues myogenic progenitor cell proliferative and regenerative capacity in Foxk1 null mice
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DOI：
10.1074/jbc.m209200200
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发表时间：
2003-02-07
影响因子：
4.8
通讯作者：
Garry, DJ
中科院分区：
文献类型：
--
作者：
Hawke, TJ;Jiang, N;Garry, DJ
Foxk 1是一个叉头/翼状螺旋转录因子，仅限于成人骨骼肌中的肌源性祖细胞。缺乏Foxk 1（Foxk 1-/-）的小鼠在损伤后表现出生长迟缓和骨骼肌再生严重受损。在这里，我们发现Foxk 1-/-小鼠的肌源性祖细胞数量减少，细胞周期进程受到干扰（G（0）/G（1）停滞）。Foxk 1-/-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，与其他细胞周期抑制剂（包括p53）的变化无关。Foxk 1-/-小鼠与p21（CIP）-/-小鼠的组合交配产生双突变后代，导致Foxk 1-/-小鼠特征性的生长缺陷、骨骼肌再生、肌源性祖细胞数量和细胞周期进展的完全恢复。我们的结论是，Foxk 1是必不可少的调节细胞周期进程中的肌祖细胞和细胞周期蛋白依赖性激酶抑制剂，p21（CIP），可能是Foxk 1的下游目标。
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.