Dominant Negative Mutants of Transforming Growth Factor-beta 1 Inhibit the Secretion of Different Transforming Growth Factor-beta Isoforms

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1992 Apr 1

PMID 1549120

Citations 11

Authors

A R Lopez

J Cook

P L Deininger

R Derynck

Affiliations

Soon will be listed here.

Abstract

Transforming growth factor-beta (TGF-beta) is a secreted polypeptide factor that is thought to play a major role in the regulation of proliferation of many cell types and various differentiation processes. Several related isoforms have been structurally characterized, three of which, TGF-beta 1, -beta 2, and -beta 3, have been detected in mammalian cells and tissues. Each TGF-beta form is a homodimer of a 112-amino-acid polypeptide which is encoded as a larger polypeptide precursor. We have introduced several mutations in the TGF-beta 1 precursor domain, resulting in an inhibition of TGF-beta 1 secretion. Coexpression of these mutants with wild-type TGF-beta 1, -beta 2, and -beta 3 results in a competitive and specific inhibition of the secretion of different TFG-beta forms, indicating that these mutated versions act as dominant negative mutants for TGF-beta secretion. Overexpression of dominant negative mutants can thus be used to abolish endogenous secretion of TGF-beta and structurally related family members, both in vitro and in vivo, and to probe in this way the physiological functions of the members of the TGF-beta superfamily.

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References

Beckmann R, Mizzen L, Welch W . Interaction of Hsp 70 with newly synthesized proteins: implications for protein folding and assembly. Science. 1990; 248(4957):850-4. DOI: 10.1126/science.2188360. View

Pelton R, Hogan B, Miller D, Moses H . Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation. Dev Biol. 1990; 141(2):456-60. DOI: 10.1016/0012-1606(90)90401-4. View

Ozkaynak E, Rueger D, Drier E, Corbett C, Ridge R, Sampath T . OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J. 1990; 9(7):2085-93. PMC: 551926. DOI: 10.1002/j.1460-2075.1990.tb07376.x. View

Mason A, Hayflick J, Ling N, Esch F, Ueno N, Ying S . Complementary DNA sequences of ovarian follicular fluid inhibin show precursor structure and homology with transforming growth factor-beta. Nature. 1985; 318(6047):659-63. DOI: 10.1038/318659a0. View

Graycar J, Miller D, Arrick B, Lyons R, Moses H, Derynck R . Human transforming growth factor-beta 3: recombinant expression, purification, and biological activities in comparison with transforming growth factors-beta 1 and -beta 2. Mol Endocrinol. 1989; 3(12):1977-86. DOI: 10.1210/mend-3-12-1977. View

Purchio A, Cooper J, Brunner A, Lioubin M, Gentry L, Kovacina K . Identification of mannose 6-phosphate in two asparagine-linked sugar chains of recombinant transforming growth factor-beta 1 precursor. J Biol Chem. 1988; 263(28):14211-5. View

SMITHIES O, Gregg R, Boggs S, Koralewski M, Kucherlapati R . Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature. 1985; 317(6034):230-4. DOI: 10.1038/317230a0. View

Miyazono K, Hellman U, Wernstedt C, Heldin C . Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization. J Biol Chem. 1988; 263(13):6407-15. View

Ten Dijke P, Hansen P, Iwata K, Pieler C, Foulkes J . Identification of another member of the transforming growth factor type beta gene family. Proc Natl Acad Sci U S A. 1988; 85(13):4715-9. PMC: 280506. DOI: 10.1073/pnas.85.13.4715. View

10.

Wozney J, Rosen V, Celeste A, Mitsock L, Whitters M, Kriz R . Novel regulators of bone formation: molecular clones and activities. Science. 1988; 242(4885):1528-34. DOI: 10.1126/science.3201241. View

11.

Derynck R, Lindquist P, Lee A, Wen D, TAMM J, Graycar J . A new type of transforming growth factor-beta, TGF-beta 3. EMBO J. 1988; 7(12):3737-43. PMC: 454948. DOI: 10.1002/j.1460-2075.1988.tb03257.x. View

12.

Gentry L, Webb N, Lim G, Brunner A, Ranchalis J, Twardzik D . Type 1 transforming growth factor beta: amplified expression and secretion of mature and precursor polypeptides in Chinese hamster ovary cells. Mol Cell Biol. 1987; 7(10):3418-27. PMC: 367992. DOI: 10.1128/mcb.7.10.3418-3427.1987. View

13.

Zoller M, Smith M . Oligonucleotide-directed mutagenesis: a simple method using two oligonucleotide primers and a single-stranded DNA template. DNA. 1984; 3(6):479-88. DOI: 10.1089/dna.1.1984.3.479. View

14.

Gorman C, Padmanabhan R, Howard B . High efficiency DNA-mediated transformation of primate cells. Science. 1983; 221(4610):551-3. DOI: 10.1126/science.6306768. View

15.

Graham F, Smiley J, Russell W, Nairn R . Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977; 36(1):59-74. DOI: 10.1099/0022-1317-36-1-59. View

16.

Panganiban G, Rashka K, Neitzel M, Hoffmann F . Biochemical characterization of the Drosophila dpp protein, a member of the transforming growth factor beta family of growth factors. Mol Cell Biol. 1990; 10(6):2669-77. PMC: 360626. DOI: 10.1128/mcb.10.6.2669-2677.1990. View

17.

Lee S . Identification of a novel member (GDF-1) of the transforming growth factor-beta superfamily. Mol Endocrinol. 1990; 4(7):1034-40. DOI: 10.1210/mend-4-7-1034. View

18.

Ueno H, Colbert H, Escobedo J, Williams L . Inhibition of PDGF beta receptor signal transduction by coexpression of a truncated receptor. Science. 1991; 252(5007):844-8. DOI: 10.1126/science.1851331. View

19.

Gatenby A, Ellis R . Chaperone function: the assembly of ribulose bisphosphate carboxylase-oxygenase. Annu Rev Cell Biol. 1990; 6:125-49. DOI: 10.1146/annurev.cb.06.110190.001013. View

20.

Gatherer D, Ten Dijke P, Baird D, Akhurst R . Expression of TGF-beta isoforms during first trimester human embryogenesis. Development. 1990; 110(2):445-60. DOI: 10.1242/dev.110.2.445. View