Genomic instability in the type II TGF-beta1 receptor gene in atherosclerotic and restenotic vascular cells.
Cells proliferating from human atherosclerotic lesions are resistant to the antiproliferative effect of TGF-beta1, a key factor in wound repair. DNA from human atherosclerotic and restenotic lesions was used to test the hypothesis that microsatellite instability leads to specific loss of the Type II receptor for TGF-beta1 (TbetaR-II), causing acquired resistance to TGF-beta1. High fidelity PCR and restriction analysis was adapted to analyze deletions in an A10 microsatellite within TbetaR-II. DNA from lesions, and cells grown from lesions, showed acquired 1 and 2 bp deletions in TbetaR-II, while microsatellites in the hMSH3 and hMSH6 genes, and hypermutable regions of p53 were unaffected. Sequencing confirmed that these deletions occurred principally in the replication error-prone A10 microsatellite region, though nonmicrosatellite mutations were observed. The mutations could be identified within specific patches of the lesion, while the surrounding tissue, or unaffected arteries, exhibited the wild-type genotype. This microsatellite deletion causes frameshift loss of receptor function, and thus, resistance to the antiproliferative and apoptotic effects of TGF-beta1. We propose that microsatellite instability in TbetaR-II disables growth inhibitory pathways, allowing monoclonal selection of a disease-prone cell type within some vascular lesions.
McCaffrey
T A
TA
Department of Medicine, Cornell University Medical College-The New York Hospital, New York 10021, USA. tamccaf@med.cornell.edu
Du
B
B
Consigli
S
S
Szabo
P
P
Bray
P J
PJ
Hartner
L
L
Weksler
B B
BB
Sanborn
T A
TA
Bergman
G
G
Bush
H L
HL
D001161:Arteriosclerosis / Q000235:genetics* / Q000473:pathology; D017073:Atherectomy; D001483:Base Sequence; D002478:Cells, Cultured; D003331:Coronary Vessels; D006801:Humans; D008323:Mammary Arteries; D018895:Microsatellite Repeats; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012307:Risk Factors
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II