Absence of p21CIP Rescues Myogenic Progenitor Cell Proliferative and Regenerative Capacity in Foxk1 Null Mice

Abstract

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.

JNK-associated Leucine Zipper Protein Functions as a Docking Platform for Polo-like Kinase 1 and Regulation of the Associating Transcription Factor Forkhead Box Protein K1

“…7C). These results are consistent with previous reports that demonstrated FOXK1-mediated repression of p21 gene expression and increased proliferation in the C2C12 myoblast cell line (45). Furthermore, we performed immunoblotting of cell lysates derived from asynchronous and mitotic cells expressing control Protein lysates from these cells were immunoblotted (IB) using the indicated antisera.…”

“…PLK1 has been shown to phosphorylate and regulate the localization and transcriptional function of various FOX transcription factors, FOXM1 (39), FOXO1 (40), and FOXO3 (41). Although FOXK1 is implicated as a regulator of myogenic proliferation (21,(43)(44)(45), little is known about its function during mitosis. Previous studies have shown that CYCLIN-CDK complexes phosphorylate FOXK2, a protein that is highly homologous to FOXK1, during mitosis and that such phosphorylation regulates its stability and transcriptional function (20).…”

Regulation of myoglobin expression

“…However, it should be noted here that Sp1 is not the only transcription factor believed to recognize the CCAC-box motif. Data by the Williams laboratory suggest that the myocyte nuclear factor (MNF), a member of the winged-helix family of transcription factors, also recognizes this DNA-binding motif and serves a role in myogenesis and muscle regeneration (Bassel-Duby et al, 1994;Garry et al, 2000;Garry et al, 1997;Hawke et al, 2003;Meeson et al, 2007;Shi et al, 2010;Yang et al, 1997;Yang et al, 2000). However, to date there are no detailed studies investigating the role of MNF in modulating myoglobin transcriptional activity.…”

Expression of connexins during differentiation and regeneration of skeletal muscle: functional relevance of connexin43

“…-/- (Hawke et al, 2003), Pop1 -/- (Andrée et al, 2002) and Slug -/- mice. Similarly, we report here that specific deletion of Cx43 delays regeneration by >7 days.…”