Transmembrane TGF-α precursors activate EGF/TGF-α receptors

Brachmann, Rainer K.; Lindquist, Patricia B.; Nagashima, Mariko; Kohr, William J.; Lipari, Terry; Napier, Mary E.; Derynck, Rik

doi:10.1016/0092-8674(89)90591-6

Cited by 402 publications

(223 citation statements)

References 41 publications

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“…It is produced as a transmembrane protein from which the active 50 amino acid peptide is cleaved at the extracellular surface. In addition, there is evidence that the transmembrane precursor has biological activity (Wong et al, 1989;Brachmann et al, 1989). Typically, EGFR binding initiates a signal for the cell to divide.…”

Section: Tgfa and C-myc In Human Breast Cancermentioning

confidence: 99%

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

Rose-Hellekant

Sandgren

2000

Oncogene

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The growth factor transforming growth factor alpha (TGFa) and the nuclear transcription factor c-myc often are overexpressed by human breast cancer cells. To produce models of breast disease with these etiologies, mice were generated that carried TGF-a-or c-mycencoding transgenes. Transgene targeting employed the whey acidic protein (WAP) gene promoter, which is expressed in pregnant and lactating mammary epithelial cells. Non-virgin WAP-TGFa transgenic mice displayed accelerated mammary development during pregnancy, delayed post-parturient mammary involution, a progressive increase in the number of hyperplastic alveolar nodules (HANs), and development of mammary carcinoma with a mean latency of 9 months. Non-virgin WAP-c-myc transgenic mice displayed accelerated mammary gland development during pregnancy and development of mammary carcinomas with a latency of 8 months. Bitransgenic mice carrying both WAP-TGFa and WAPc-myc displayed a dramatic acceleration of tumor development. These models identify the overexpression of TGFa or c-myc as etiological factors in the development of mammary neoplasia and demonstrate the increased severity of disease when both molecular alterations are present in the same cell.

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Section: Tgfa and C-myc In Human Breast Cancermentioning

confidence: 99%

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

Rose-Hellekant

Sandgren

2000

Oncogene

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“…VHL acts by decreasing TGF-a mRNA stability (Knebelmann et al, 1998). In several human tumor-derived cell lines that express endogenous TGFa and EGF receptor, membrane-bound proTGF-a represents a signi®cant portion of the total TGF-a expressed (Brachmann et al, 1989;Ezzat et al, 1995;Baselga et al, 1996;Seki et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Human keratinocytes and tumor-derived cell lines express alternatively spliced forms of transforming growth factor-α mRNA, encoding precursors lacking carboxyl-terminal valine residues

Liao

Creek

et al. 1999

Oncogene

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The human transforming growth factor-alpha (TGF-a) gene is thought to contain ®ve introns and six exons, encoding a transmembrane precursor (proTGF-a) from which the mature polypeptide is released by proteolytic cleavage. We identi®ed a novel 32-nucleotide exon (exon a) within intron 5 and an alternative splice acceptor site in exon 6, splitting exon 6 into two segments: 6A and 6B. Therefore, in addition to wild type (wt) proTGF-a mRNA, which skips exon a, two novel proTGF-a variants are produced: Variant I (VaI), skipping exons a and 6A, and Variant II (VaII) which includes exon a and skips exon 6A. The only signi®cant di erence between variant and wt proTGF-a proteins is that the two wt carboxyl-terminal valines are replaced in the variants by ®ve or four other amino acids, respectively. Both variant TGF-a mRNAs were readily detected in human keratinocytes and tumor-derived cell lines. Their protein products were cleaved as e ciently as wt TGF-a in response to the calcium ionophore A23187. However, both variants (but not wt) reduced serum requirements for proliferation in CHO cells. In addition, VaIIexpressing CHO cells (not VaI or wt) formed foci in monolayer cultures. These results suggest that variant TGF-a precursors induce autonomous growth.

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“…Similarly, Kumar and Mendelsohn (1990) have shown that treatment of A43 1 cells with IFN-y enhances expression of TGF-m. In addition, IFN-y inhibits growth of human keratinocytes, decreases EGF binding, and increases TGF-a production (Nickloff & Mitra, 1989 (Brachmann et al, 1989). Increased secretion of TGF-o could also be responsible for the IFN-y induced stimulation of EGFR synthesis, as TGF-a enhances EGFR synthesis in the cell line (Bjorge et al, 1989).…”

Section: Cell Culturementioning

confidence: 99%

Increased epidermal growth factor receptor gene expression by γ-interferon in a human breast carcinoma cell line

Hamburger

Pinnamaneni²

1991

Br J Cancer

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Summary The interferons are a group of naturally occuring proteins that inhibit the growth of tumours in vivo and many transformed cell lines in vitro. The mechanisms of action of interferon, however, remain unclear. The IFN induced inhibition of growth of many epithelial cancer cell lines is associated with changes Interferons are a family of secretory cellular proteins with a wide range of biological effects. In addition to their antiviral activity, IFNs inhibit growth of both normal and transformed cells (Balkwill et al., 1982; Bradley & Ruscetti, 1981 (Chakravarthy et al., 1991). The purpose of the present study was to examine the effect of IFN on synthesis and stability of the EGFR protein and mRNA. Materials and methods Cell cultureThe MDA 468 cell line (kindly provided by Dr Ron Buick, Ontario Cancer Institute) was derived from a human breast carcinoma (Filmus et al., 1985). It was routinely cultured in L-15 medium (Gibco) supplemented with 10% foetal bovine serum (FBS) (Sigma, St Louis, MO). Cells were subcultured twice weekly by trypsinisation. All cells were used within 20 passages of the original stock.Protein labelling and immunoprecipitation MDA 468 cells (6 x 105 total) were plated in 75 cm2 flasks in 50% DMEM, 50% F-12 medium with 10% calf-serum. Medium were aspirated, the cells rinsed with methionine-free RPMI (ABS, Columbia, MD) and incubated for 6 h with "5Smethionine (38 piCi ml-') (S.A. 1129 Ci mmol-') (New England Nuclear, Boston, MA) in 5ml methionine free RPMI. Cells were lysed in 1 ml of 50 mM Tris HCI, Triton X-100 (1% v/v), SDS (0.1% w/v), PMSF (1 mM), EDTA (1 mM) and leupeptin (1 ,Ag ml-') at room temperature. Cell lysates were centrifuged and duplicate aliquots of each lysate were standardised by trichloroacetic acid precipitation. The samples were then incubated with a monoclonal antibody to EGF receptor (antibody 528) (final concentration of 1.5 jig ml-') (Oncogene Science Inc, Mineola, NY) or a non-specific antibody of the same isotype and Protein-A Sepharose. Bound material was released by heating the complexes in SDS buffer for 2 min at 100°C. The samples were then analysed on 7.5% SDS polyacrylamide gels. Following electrophoresis, the gels were treated with Enhance (NEN) and dried. The gels were exposed to Kodak XAR-5 film and developed. Where indicated, the relative amounts of immunoprecipitated EGF receptor were quantitated by densitometric analysis of the autoradiograms using a LKB laser Correspondence: A.W. Hamburger.

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Transmembrane TGF-α precursors activate EGF/TGF-α receptors

Cited by 402 publications

References 41 publications

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

Human keratinocytes and tumor-derived cell lines express alternatively spliced forms of transforming growth factor-α mRNA, encoding precursors lacking carboxyl-terminal valine residues

Increased epidermal growth factor receptor gene expression by γ-interferon in a human breast carcinoma cell line

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