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Molecular and Cellular Biology, October 2001, p. 6927-6938, Vol. 21, No. 20
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.20.6927-6938.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Molecular Basis for Impaired Muscle Differentiation
in Myotonic Dystrophy
Nikolai A.
Timchenko,1,2
Polina
Iakova,1
Zong-Jin
Cai,3
James R.
Smith,1,3,4,5 and
Lubov T.
Timchenko3,6,*
Huffington Center on
Aging1 and Departments of
Pathology,2
Medicine,3 Molecular
Virology,4 Cell
Biology,5 and Molecular Physiology and
Biophysics,6 Baylor College of Medicine,
Houston, Texas 77030
Received 10 May 2001/Accepted 11 July 2001
Differentiation of skeletal muscle is affected in myotonic
dystrophy (DM) patients. Analysis of cultured myoblasts from DM patients shows that DM myoblasts lose the capability to withdraw from
the cell cycle during differentiation. Our data demonstrate that the
expression and activity of the proteins responsible for cell cycle
withdrawal are altered in DM muscle cells. Skeletal muscle cells from
DM patients fail to induce cytoplasmic levels of a CUG RNA binding
protein, CUGBP1, while normal differentiated cells accumulate CUGBP1 in
the cytoplasm. In cells from normal patients, CUGBP1 up-regulates p21
protein during differentiation. Several lines of evidence show that
CUGBP1 induces the translation of p21 via binding to a GC-rich sequence
located 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 alterations of other proteins responsible for the cell cycle
withdrawal. The activity of cdk4 declines during differentiation of
cells from control patients, while in DM cells cdk4 is highly active
during all stages of differentiation. In addition, DM cells do not form Rb/E2F repressor complexes that are abundant in differentiated cells
from normal patients. Our data provide evidence for an impaired cell
cycle withdrawal in DM muscle cells and suggest that alterations in the
activity of CUGBP1 causes disruption of p21-dependent control of cell
cycle arrest.
*
Corresponding author. Mailing address: Department of
Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX
77030. Phone: (713) 798-6911. Fax: (713) 798-3142. E-mail:
lubovt{at}bcm.tmc.edu.
Molecular and Cellular Biology, October 2001, p. 6927-6938, Vol. 21, No. 20
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.20.6927-6938.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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