A synthetic fragment of rat transforming growth factor α with receptor binding and antigenic properties

Nestor, John J.; Newman, Sherry R.; DeLustro, Barbara; Todaro, George J.; Schreiber, Alain B.

doi:10.1016/0006-291x(85)91426-3

Cited by 84 publications

(28 citation statements)

References 11 publications

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“…These data indicate that MCV DNA has the potential to encode the conserved heptapeptide responsible for receptor binding by EGF-like peptides (Nestor et al, 1985). We propose that MCV encodes a growth factor that is analogous to EGF and is responsible for cell proliferation and tumourigenesis.…”

Section: Discussionmentioning

confidence: 90%

“…All six cysteine residues are invariant and the pattern of disulphide bridges linking these residues is indicated above the sequence data (Savage et al, 1973). The conserved region indicated below (hEGF residues 36 to 42) comprises the third disulphide loop and has been implicated in receptor binding (Nestor et al, 1985). It is a sequence of seven residues of which five are invariant.…”

Section: Oligonucleotide Design and Hybridizationsmentioning

confidence: 99%

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Characterization and Physical Mapping of Molluscum Contagiosum Virus DNA and Location of a Sequence Capable of Encoding a Conserved Domain of Epidermal Growth Factor

Porter

Archard

1987

Journal of General Virology

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SUMMARYDNA from Molluscum contagiosum virus (MCV) isolates was analysed by restriction endonuclease cleavage, revealing two virus subtypes. Physical maps of cleavage sites for BamHI, Clal and HindIII were constructed, and found to differ extensively between the two subtypes. MCV DNA was similar to Orthopoxvirus DNA with respect to size, terminal cross-linking and the presence of inverted terminal repetitions, but did not hybridize with vaccinia virus DNA. The genomes of the two MCV subtypes crosshybridized and were colinear except for two small regions. There was sequence homology between DNA from corresponding map regions of the MCV subtypes but, in contrast to Orthopoxvirus DNA, no conservation of restriction sites. A synthetic oligonucleotide probe representing a conserved domain of epidermal growth factor, c~-transforming growth factor and the vaccinia growth factor identified equivalent regions of both MCV genomes as having the potential to encode this domain. This locus is similar to the position of the vaccinia growth factor gene in vaccinia virus DNA. Thus MCV may induce epidermal cell proliferation and tumourigenesis by expression of an epidermal growth factor-like polypeptide. INTRODUCTIONMolluscum contagiosum virus (MCV) is an unclassified poxvirus of man which induces benign skin tumours. Transmission is mechanical and, in adults, may be venereal. The skin lesion consists of a localized mass of hypertrophied and hyperplastic epidermis extending down into the underlying dermis and projecting above the surface as a papule. The rate of cell division in the basal layer is several times that of normal skin. The lower cells of the stratum spinosum contain characteristic cytoplasmic inclusion bodies resulting from virus replication, which enlarge as the infected cells migrate through the stratum granulosum towards the surface. These molluscum bodies are trapped in the horny layer by a fibrous network which dissolves in the centre of the lesion forming a central core composed primarily of virus. The disease is selflimiting but lesions may be curetted or the virus-rich core collected. Attempts to propagate virus in vitro have not been successful (Postlethwaite, 1970). Parr et al. (1977) studied the MCV genome by electron microscopy and showed by partial denaturation that it is a terminally cross-linked molecule of about 180 kb. They also demonstrated three different BamHI cleavage patterns of DNA from MCV isolates. Dural et aL (1986) have reported two viral subtypes on the basis of different cleavage patterns.MCV is one of several tumourigenic poxviruses. Others are Shope rabbit fibroma virus and Yaba monkey tumour virus which induce fibromas and histiocytomas respectively. Induction of epidermal cell proliferation by poxviruses is of interest following recent studies demonstrating that a vaccinia virus Mr 19 000 (19K) polypeptide is structurally and functionally homologous to epidermal growth factor (EGF) and to c~-transforming growth factor (~-TGF) (Brown et al.,

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Section: Discussionmentioning

confidence: 90%

Section: Oligonucleotide Design and Hybridizationsmentioning

confidence: 99%

Characterization and Physical Mapping of Molluscum Contagiosum Virus DNA and Location of a Sequence Capable of Encoding a Conserved Domain of Epidermal Growth Factor

Porter

Archard

1987

Journal of General Virology

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“…We chose to place TGF-a at the COOH end of P because the NH2 terminus of EGF, a molecule with a vei similar structure to TGF-a, can be modified without signi icant loss of activity (3). This is probably because ti receptor binding activity ofTGF-a lies in the C disulfide looj at the COOH-terminal portion of the molecule (19).…”

Section: Discussionmentioning

confidence: 99%

Activity of a recombinant fusion protein between transforming growth factor type alpha and Pseudomonas toxin.

Chaudhary¹,

FitzGerald²,

Pastan³

1987

Proc. Natl. Acad. Sci. U.S.A.

157

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Pseudomonas exotoxin has been crystallized, and x-ray diffraction analysis of the crystal structure of PE shows that the toxin is composed of three distinct domains (7). Using the three-dimensional structure as a guide, deletion mutants of the PE structural gene were constructed and the proteins were encoded by the different domains of PE expressed in Escherichia coli (8). These studies have shown that domain I of PE is responsible for cell recognition, domain II is responsible for translocation of the toxin across membranes, and domain III is responsible for ADP-ribosylation of elongation factor 2, the step actually responsible for cell death (Fig. 1) (3.7 kb) was ligated to the 155-bp fragment. Restriction analysis using BamHI and Sph I was used to identify the plasmid with TGF-a gene in the proper orientation (pVC33).

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“…Using synthetic peptides corresponding to the various loops of rat TGF-a, Nestor et al (30) showed that a peptide fragment corresponding to loop C was slightly active in EGF receptor binding (0.2% that of intact EGF), whereas fragments corresponding to other regions of TGF-a were inactive. However, similar work by Komoriya et al (24) with synthetic peptide fragments of mouse EGF and by DefeoJones et al (13) with synthetic peptide fragments from human TGF-a showed no ability for loop C fragments to bind to the EGF receptor.…”

mentioning

confidence: 99%

Aromaticity at position 37 in human epidermal growth factor is not obligatory for activity.

Engler¹,

Hauser²,

Cook³

et al. 1991

Mol. Cell. Biol.

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The third disulfide loop (amino acids 33 to 42) of human epidermal growth factor (hEGF) encompasses the region of highest amino acid conservation among all of the EGF-like family of molecules. The importance of some of these highly conserved residues for the maintenance of biological activity, especially the aromatic amino acid tyrosine at position 37, has until now been considered essential on the basis of previous studies with the EGF-like molecule transforming growth factor alpha. Variants at the Tyr-37 position of hEGF were constructed by site-directed mutagenesis. The substituting amino acids were phenylalanine, histidine, serine, alanine, aspartic acid, arginine, and glycine. The variants were tested for their ability to competitively displace native ['25I]hEGF from its receptor and to stimulate the protein-tyrosine kinase activity of the receptor; the order of efficacy of substituting amino acids was Phe > His > Ser > Ala > Asp > Arg > Gly in both assays. All were effective, with no or only moderate reduction in potency, in stimulating the incorporation of [3H]thymidine into acid-insoluble material of quiescent mouse A31 cells. Only Tyr-37-*Ala, Tyr-37--Arg and Tyr-37-*Gly were slightly less potent in the cell assay. Thus, neither tyrosine nor another aromatic amino acid at position 37 in hEGF is essential for full biological activity.

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A synthetic fragment of rat transforming growth factor α with receptor binding and antigenic properties

Cited by 84 publications

References 11 publications

Characterization and Physical Mapping of Molluscum Contagiosum Virus DNA and Location of a Sequence Capable of Encoding a Conserved Domain of Epidermal Growth Factor

Characterization and Physical Mapping of Molluscum Contagiosum Virus DNA and Location of a Sequence Capable of Encoding a Conserved Domain of Epidermal Growth Factor

Activity of a recombinant fusion protein between transforming growth factor type alpha and Pseudomonas toxin.

Aromaticity at position 37 in human epidermal growth factor is not obligatory for activity.

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