Download MyoD as a gatekeeper to cell cycle progression

Amy Grace Harder
Biol200 – Proseminar
News And Views, Tintignac et al.
MyoD as a gatekeeper to cell cycle progression
Movement through the cell cycle is a highly coordinated process. A major mechanism
of regulating this progression is the timely transcriptional activation of genes involved in each
phase of the cell cycle. During development, MyoD directs cells fated for myoblast lineage to
exit the cell cycle and begin the differentiation process. MyoD acts similarly on these now
differentiated cells by orchestrating the temporal expression of many key genes. MyoD,
however, does not act alone. Coactivators such as p300/CBP and P/CAF facilitate
transcription probably through their histone acetyltransferase activity.
MyoD’s own protein levels are driven by changes during the cell cycle. Tintignac et al.
show MyoD expression peaks during G1 and G2, while a less abundant phosphorylated MyoD
prevails in mitosis. Cyclin B-cdc2 phosphorylates MyoD at serine 5 and serine 200 during the
G2/M transition, and Tintignac and colleagues found this event has two important
consequences.
First, phosphorylation is a negative regulator of MyoD transcriptional activation. Using
a phosphorylation mutant of MyoD, the authors observed MyoD loses its affinity for P/CAF
upon phosphorylation and instead prefers binding to histone deacetylase 1 (HDAC1), a
negative regulator of gene expression. Loss of MyoD phosphorylation resulted in delayed
entrance into mitosis. The authors propose a mechanism in which p21 accumulates in G2 in the
absence of MyoD phosphorylation. In wildtype cells, p21 binds cyclin B-Cdc2 in G2
repressing the complex’s activity. p21 levels decline rapidly upon entry into mitosis, releasing
cyclin B-Cdc2 from its inhibitory effects. An uncontrolled buildup of p21 would, therefore,
prevent cyclin B-Cdc2 from initiating mitosis.
Second, phosphorylation may be an important signal for protein degradation by the
ubiquitin/proteasome pathway. Phosphorylated MyoD is normally degraded in G2 but can be
stabilized by adding a proteasome inhibitor to cells, indicating phosphorylation to be the key
event responsible for MyoD degradation in G2. The authors further note that the half-life of
the MyoD phosphorylation mutant is approximately three times longer than wildtype MyoD.
Mutant and wildtype MyoD, however, were equally stable in mitosis, indicating there are
separate pathways leading to MyoD proteolysis in which G2 degradation in phosphorylation
dependent and mitotic degradation is phosphorylation-independent.
The recent work of Tintignac and colleagues has done much to improve the current
understanding of the role of MyoD in cell differentiation and cell cycle progression, its
opposing interactions with a histone acetyltransferase and a histone deacetylase, and finally
MyoD’s regulation of its own expression profile. Much insight as been gained, but many
questions remain. Of particular interest are the apparently different mechanisms of MyoD
proteolysis in G2 and mitosis. Whether phosphorylation elicits a conformational change that
exposes a functional D-box or whether it recruits directly or indirectly a member of the
ubiquitin pathway has yet to be elucidated.