Characterization of mutated transforming growth factor-beta s which possess unique biological properties.
Transforming growth factor-beta (TGF-beta) is a potent regulator of cell growth and differentiation. On the basis of the crystal structure of TGF-beta 2, we have designed and synthesized two mutant TGF-beta s, TGF-beta 1 (71 Trp) and TGF-beta 1 (delta 69-73). Although both of these molecules inhibited the growth of Mv1Lu mink lung epithelial cells and LS1034 colorectal cancer cells, which are affected equally by TGF-beta 1 and TGF-beta 2, TGF-beta 1 (delta 69-73) was much less potent than TGF-beta 1 or TGF-beta 1 (71 Trp) at inhibiting the growth of LS513 colorectal cancer cells which are growth-inhibited by TGF-beta 1 but not TGF-beta 2. Both TGF-beta 1 (71 Trp) and TGF-beta 1 (delta 69-73) increased levels of mRNAs for fibronectin and plasminogen activator inhibitor with Mv1Lu cells, whereas only TGF-beta 1 (71 Trp) and not TGF-beta 1 (delta 69-73) up-regulated the mRNA level of carcinoembryonic antigen in LS513 cells. The expression level of carcinoembryonic antigen mRNA in LS1034 cells was not altered by either wild-type or mutant TGF-beta s. Receptor labeling experiments demonstrated that TGF-beta 1 (71 Trp) bound with high affinity to the cell-surface receptors of Mv1Lu, LS1034, and LS513 cells while TGF-beta 1 (delta 69-73) bound effectively to the receptors of Mv1Lu and LS1034 cells but much less to the receptors on LS513 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Qian
S W
SW
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892.
Burmester
J K
JK
Sun
P D
PD
Huang
A
A
Ohlsen
D J
DJ
Suardet
L
L
Flanders
K C
KC
Davies
D
D
Roberts
A B
AB
Sporn
M B
MB
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D016466:CHO Cells; D002272:Carcinoembryonic Antigen / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015179:Colorectal Neoplasms; D006224:Cricetinae; D003432:Cross-Linking Reagents; D018360:Crystallography, X-Ray; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005240:Feasibility Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008907:Mink; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000378:metabolism; D015854:Up-Regulation
D002272:Carcinoembryonic Antigen; D003432:Cross-Linking Reagents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta