Crosstalk between cell cycle regulators and the myogenic factor MyoD in skeletal myoblasts

Abstract

During the early process of skeletal muscle differentiation, myogenic factors are not only involved in muscle-specific gene induction but also in regulating the transition from the proliferative stage, when MyoD and Myf5 are already expressed, to the orderly exit from the cell division cycle. This key step in skeletal muscle differentiation involves the down-regulation of cell cycle activators such as cyclins and cdks, and up-regulation of cell cycle inhibitors such as Rb, p21, p27, and p57. In particular, Rb and p21 have been shown to play an important role in the growth arrest of differentiating myoblasts. Their level and/or activity, while being negatively controlled by growth factors, appear to be positively linked with the myogenic factor MyoD, which plays a cooperative role in the induction of growth arrest. MyoD can block proliferation independently of its transcriptional activity. Therefore, the interplay between G1 cyclins and cdk inhibitors, on the one hand, and MyoD and its co-factors, on the other, plays a critical role in myoblast cell cycle withdrawal. Accurate synchronization of dividing myoblasts revealed that MyoD and Myf5 are themselves subject to specific cell cycle-dependent regulation, with MyoD at its highest level in early G1 and its lowest level at the G1 to S phase transition. The time-window when cells exit their cycle into differentiation is in G1, when MyoD is maximal and Myf5 is down. In contrast, quiescent non-differentiating myoblasts (i. e., in G0) present an opposite pattern for the two factors: high Myf5 and no MyoD. Several recent studies have focused on MyoD phosphorylation and its potential role in ubiquitination-mediated degradation of the protein. Linking this phosphorylation to the cell cycle-dependent drop in MyoD protein before S phase leads, to a mechanism implying cdk2-cyclin E and its inhibitors (p57kip and p21cip) in the tight control of MyoD levels and subsequent myoblast cell cycle progression or exit into differentiation.

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

“…It is also known that myoblast differentiation requires dephosphorylation of the retinoblastoma pRb protein and that underphosphorylated pRb [Markiewicz et al, 2005] increases the transcriptional ability of MyoD family of muscle gene regulatory factors [Dick, 2007]. It has been proposed that a regulatory checkpoint in the terminal cell cycle arrest of myoblasts during differentiation involves the modulation of the cyclin D cdkdependent phosphorylation of pRb through the opposing effects of cyclin D1 and MyoD [Kitzmann and Fernandez, 2001]. …”

p57Kip2 and Cancer: Time for a Critical Appraisal

“…They detected p57 Kip2 in 21 out of 33 benign cancers, 12 out of 23 borderline cancers, and 19 out of 47 ovarian carcinomas. An analysis of 171 primary tumors from previously untreated patients with advanced ovarian carcinoma (stage III) showed a frequent decrease of the protein, without any correlation with poor survival (37,124).…”

“…The N-terminal domain of p57 Kip2 is also the site of interaction with MyoD and other basic helix-loop-helix (b-HLH) transcription factors, such as Mash1, NeuroD, and Nex/Math2 (35)(36)(37)(38)(39). p57 Kip2 has also been reported to interact with Nuclear Receptor Related 1 (NURR1) protein.…”

Transcriptome Expression Profiles in Prenatal Pigs in Relation to Myogenesis

“…A network of genes affects the expression patterns of the MRF genes (Olson, 1993;Rawls and Olson, 1997;Capdevila and Johnson, 2000;Dobosy and Selker, 2001;Kitzmann and Fernandez, 2001; Lee et al, 2001;Zhu et al, 2001). By doing so they affect muscle and body growth potential.…”