We and others previously showed that p38 mitogen-activated protein kinase is 
indispensable for myogenic differentiation. However, it is less clear which of 
the four p38 isoforms in the mouse genome participates in this process. Using 
C2C12 myogenic cells as a model, we showed here that p38alpha, beta, and gamma 
are expressed with distinct expression patterns during differentiation. 
Knockdown of any of them by small interfering RNA inhibits myogenic 
differentiation, which suggests that the functions of the three p38 isoforms are 
not completely redundant. To further elucidate the unique role of each p38 
isoform in myogenic differentiation, we individually knocked down one p38 
isoform at a time in C2C12 cells, and we compared the whole-genome gene 
expression profiles by microarrays. We found that some genes are coregulated by 
all three p38 isoforms, whereas others are uniquely regulated by one particular 
p38 isoform. Furthermore, several novel p38 target genes (i.e., E2F2, cyclin D3, 
and WISP1) are found to be required for myogenin expression, which provides a 
molecular basis to explain why different p38 isoforms are required for myogenic 
differentiation.