Differentiation of skeletal muscle is affected in myotonic dystrophy (DM) p
atients. Analysis of cultured myoblasts from DM patients shows that DM myob
lasts lose the capability to withdraw from the cell cycle during differenti
ation. Our data demonstrate that the expression and activity of the protein
s responsible for cell cycle withdrawal are altered in DM muscle cells. Ske
letal muscle cells from DM patients fail to induce cytoplasmic levels of a
CUG RNA binding protein, CUGBP1, while normal differentiated cells accumula
te CUGBP1 in the cytoplasm. In cells from normal patients, CUGBP1 up-regula
tes p21 protein during differentiation. Several lines of evidence show that
CUGBP1 induces the translation of p21 via binding to a GC-rich sequence lo
cated within the 5 ' region of p21 mRNA. Failure of DM cells to accumulate
CUGBP1 in the cytoplasm leads to a significant reduction of p21 and to alte
rations of other proteins responsible for the cell cycle withdrawal. The ac
tivity of cdk4 declines during differentiation of cells from control patien
ts, while in DM cells cdk4 is highly active during all stages of differenti
ation. In addition, DM cells do not form Rb/E2F repressor complexes that ar
e abundant in differentiated cells from normal patients. Our data provide e
vidence for an impaired cell cycle withdrawal in DM muscle cells and sugges
t that alterations in the activity of CUGBP1 causes disruption of p21-depen
dent control of cell cycle arrest.