The structure of eight distinct cloned human leukocyte interferon cDNAs

Goeddel, David V.; Leung, David W. M.; Dull, Thomas J.; Gross, Mitchell; Lawn, Richard M.; McCandliss, Russell; Seeburg, Peter H.; Ullrich, Axel; Yelverton, Elizabeth; Gray, Patrick W.

doi:10.1038/290020a0

Cited by 496 publications

(193 citation statements)

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“…(c) Several cytokine genes and proto-oncogenes that contain the AUUUA consensus sequence in their 3'-UTRs. Abbreviations: Hu=human; mda-7=melanoma di erentiation associated gene-7 (Jiang et al, 1995a); a-IFN=alpha interferon (Goeddel et al, 1981); GM-CSF=granulocyte-monocyte colony stimulating factor (Wong et al, 1985); TNF=tumor necrosis factor (Nedwin et al, 1985); cFos=fos proto-oncogene (van Straaten et al, 1983) Several studies on intrinsically unstable mRNAs demonstrate that drugs, which inhibit protein synthesis, increase their stability (Raj and Pitha, 1981;Elder et al, 1984;Linial et al, 1985). The e ect of protein synthesis inhibitors was tested using cycloheximide, a compound that inhibits peptide bond formation.…”

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Regulation of mda-7 gene expression during human melanoma differentiation

2000

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Induction of irreversible growth arrest and terminal di erentiation in human melanoma cells following treatment with recombinant human ®broblast interferon (IFNb) and mezerein (MEZ) results in elevated expression of a speci®c melanoma di erentiation associated gene, mda-7. Experiments were conducted to de®ne the mechanism involved in the regulation of mda-7 expression in di erentiating human melanoma cells. The mda-7 gene is actively transcribed in uninduced HO-1 human melanoma cells and the rate of transcription of mda-7 is not signi®cantly enhanced by treatment with IFN-b, MEZ or IFN-b+MEZ. The high basal activity of the mda-7 promoter in uninduced melanoma cells and the absence of enhancing e ect upon treatment with di erentiation inducers is corroborated by transfection studies using the promoter region of mda-7 linked to a luciferase reporter gene containing the SV40 polyadenylation signal sequence. RT ± PCR analysis detects the presence of low levels of mda-7 transcripts in uninduced and concomitant increases in di erentiation inducer treated HO-1 cells. However, steady-state mda-7 mRNA is detected only in IFN-b+MEZ and to a lesser degree in MEZ treated cells. We show that induction of terminal di erentiation of HO-1 cells with IFN-b+MEZ dramatically increases the half-life of mda-7 mRNA while treatment with cycloheximide results in detectable mda-7 mRNA in control and inducer treated cells. These observations con®rm constitutive activity of the mda-7 promoter in HO-1 cells irrespective of di erentiation status suggesting posttranscriptional processes as important determinants of mda-7 expression during terminal di erentiation. The 3' UTR region of mda-7 contains AU-rich elements (ARE) that contribute to rapid mda-7 mRNA turnover during proliferation and reversible di erentiation, a process controlled by a labile protein factor(s). Substitution of the SV40 polyadenylation signal sequence in the luciferase reporter plasmid with the mda-7-ARE-3'-UTR renders the Luciferase message unstable when expressed in proliferating and reversibly di erentiated melanoma cells. In contrast, the luciferase message is stabilized when the mda-7-ARE-3'-UTR construct is expressed in terminally di erentiated HO-1 cells. These results provide compelling evidence that mda-7 expression during terminal di erentiation in human melanoma cells is regulated predominantly at a posttranscriptional level. Oncogene (2000) 19, 1362±1368.

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Regulation of mda-7 gene expression during human melanoma differentiation

2000

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“…We report here the partial amino acid sequence ofmajor species ofhuman leukocyte interferon. These proteins, which represent a significant fraction of the active interferon produced by these cells, lack the 10 COOH-terminal amino acids suggested previously (11)(12)(13)(14) from the DNA sequences. Each of the three species is active although lacking the 10 COOH-terminal amino acids.…”

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“…Both of these residues were determined from leukocyte interferon a1. Because position 1 is Cys in all our recombinant cDNA and genomic clones (14,16,17) and those of Nagata et al (15), we assume the Ser found by us (7) and Zoon et al (6) may represent an artifact of the microsequencing procedures or modifications of the protein introduced during production and isolation. Although no NH2-terminal cysteine has been found in any of the natural leukocyte interferons (6,7,9), we have found Cys at the NH2 terminus of IFLrA produced inEscherichia coli (31,32).…”

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confidence: 76%

“…Recombinant bacterial plasmids containing interferon cDNAs have been analyzed and reveal different restriction maps and DNA sequences (10)(11)(12)(13)(14). Extensive nucleic acid sequence determination of interferon cDNAs from a virus-induced myeloblast cell line indicates that at least eight distinct species of leukocyte interferon are transcribed during the induction process (14), and this result is corroborated by restriction endonuclease mapping ofinterferon sequences in a human gene bank (15)(16)(17). All of these reports suggest that every active species of human leukocyte interferon is 165 or 166 amino acids in length, even though many individual amino acid assignments differ within the family of proteins.…”

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confidence: 99%

“…We have purified and characterized 10 interferon proteins produced by these cells: a,, a2, f31, P2, 83, and Y1, y2 y3, y4, and y5 (8). The (11)(12)(13)(14) and protein (9) sequence analysis.…”

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Amino acid sequence of a human leukocyte interferon.

Levy¹,

Rubinstein²,

Shively³

et al. 1981

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

102

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The primary structures of three major species of human leukocyte. interferon differ from the structure predicted from the DNA sequence of recombinants containing leukocyte interferon-coding regions. Compared to the recombinant interferon produced in bacteria, three of the purified natural proteins isolated from leukocytes lack the 10 COOH-terminal amino acids suggested by the DNA sequence.Although interferon was discovered 23 years ago (1), the structure of the genes and proteins are only now being elucidated with the aid of recombinant DNA technology, DNA sequence analysis, and advances in protein purification and sequence determination. These results indicate that human leukocyte interferon consists of a family of proteins with similar primary structures.Sensitive methods for protein sequence analysis at the nanomole level (2-5) have revealed NH2-terminal amino acid sequences for lymphoblastoid (6) and leukocyte (7) interferon that differ in 2 out of 20 positions. Powerful protein purification techniques involving high-performance liquid chromatography (HPLC) have been used to resolve at least 10 different species of human leukocyte interferon, and tryptic maps of this family of proteins exhibit remarkable homology (8). Amino acid sequence analysis of tryptic and chymotryptic peptides from human lymphoblastoid interferon suggests the existence ofat least five species (9).The successful cloning of human leukocyte interferon has provided additional evidence in support of this diversity. Recombinant bacterial plasmids containing interferon cDNAs have been analyzed and reveal different restriction maps and DNA sequences (10-14). Extensive nucleic acid sequence determination of interferon cDNAs from a virus-induced myeloblast cell line indicates that at least eight distinct species of leukocyte interferon are transcribed during the induction process (14), and this result is corroborated by restriction endonuclease mapping ofinterferon sequences in a human gene bank (15)(16)(17). All of these reports suggest that every active species of human leukocyte interferon is 165 or 166 amino acids in length, even though many individual amino acid assignments differ within the family of proteins. We report here the partial amino acid sequence ofmajor species ofhuman leukocyte interferon. These proteins, which represent a significant fraction of the active interferon produced by these cells, lack the 10 COOH-terminal amino acids suggested previously (11-14) from the DNA sequences. Each of the three species is active although lacking the 10 COOH-terminal amino acids.EXPERIMENTAL PROCEDURES Human leukocyte interferon species a,, a2, and 81 were isolated and purified from chronic myelogenous leukemia (CML) cells as has been described (8,(18)(19)(20). Samples of interferon (7-12 nmol) were digested with tosylphenylalanine chloromethyl ketone-treated trypsin (TPCK-trypsin, 0.2 nmol, Worthington) for 19 hr at 370C in 50 ul of 0.2 M NaHCO3. Then, 2-mercaptoethanol (2 pb1) was added and the sample was incubated for 1 hr at 37...

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Preclinical and clinical studies of interferons and interferon inducers in breast cancer

Borden¹,

Balkwill²

1984

Cancer

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Preclinical and clinical studies suggest interferons and interferon inducers have antitumor activity for breast carcinoma. Observations include inhibition of growth of freshly derived and continuously passaged breast carcinoma cells in vitro, decreased tumor size and increased survival in spontaneous mouse mammary carcinoma, inhibition of growth of xenogeneic human breast carcinomas grown in nude mice, and reduction of measurable tumors in women. Since clinical doses and schedules have to date been largely empirically derived, additional studies will be required to define optimal clinical use. Furthermore, not all interferon types or subtypes may prove clinically effective. Therefore, use of interferons or interferon inducers in patients should remain restricted to controlled trials with well‐defined research objectives.

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The structure of eight distinct cloned human leukocyte interferon cDNAs

Cited by 496 publications

References 41 publications

Regulation of mda-7 gene expression during human melanoma differentiation

Regulation of mda-7 gene expression during human melanoma differentiation

Amino acid sequence of a human leukocyte interferon.

Preclinical and clinical studies of interferons and interferon inducers in breast cancer

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