Coexpression of the sis and myc proto-oncogenes in developing human placenta suggests autocrine control of trophoblast growth

Goustin, Anton Scott; Betsholtz, Christer; Pfeifer-Ohlsson, Susan; Persson, Håkan; Rydnert, Jan; Bywater, Margaret; Holmgren, Gösta; Heldin, Carl‐Henrik; Westermark, Bengt; Ohlsson, Rolf

doi:10.1016/0092-8674(85)90083-2

Cited by 306 publications

(102 citation statements)

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“…The human c-sis gene is specifically expressed in very diverse cell-types, such as placental cytotrophoblasts (Goustin et al, 1985), bone marrow megakaryocytes (Gladwin et al, 1990), vascular endothelial cells (DiCorleto and BowenPope, 1983) and smooth muscle cells (Seifert et al, 1984). Previous studies indicated that the amount of 3.5-kb c-sis mRNA is mainly regulated at the transcription level (Colamonici et al, 1986;Daniel and Fen, 1988;Kavanaugh et al, 1988;Harsh et al, 1989;Press et al, 1988;Dirks et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that PDGF B could also play a role in the etiology and/or maintainance of epithelial tumors in vivo. c-sis mRNA is expressed in a variety of normal cells, such as placental cytotrophoblasts (Goustin et al, 1985), activated monocytes (Martinet et al, 1986), vascular endothelial cells (DiCorleto and Bowen-Pope, 1983) and smooth muscle cells (Seifert et al, 1984). Blood platelets, from which PDGF was originally purified, lack transcriptional machinery.…”

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confidence: 99%

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DNase‐I‐hypersensitive sites located far upstream of the human c‐sis/PDGF‐B gene comap with transcriptional enhancers and a silencer and are preceded by (part of) a new transcription unit

Dirks

Jansen

Onnekink

et al. 1993

European Journal of Biochemistry

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The human c-sis gene encodes the B chain of platelet-derived growth factor (PDGF), a potent mitogen for cultured cells of mesenchymal origin. PDGF is stored in the a-granules of blood platelets, which are derived from bone marrow megakaryocytes and lack transcriptional machinery. Human myeloid leukemia cell line K562 can be used as a model for megakaryocytes. Phorbol-estermediated megakaryocytic differentiation of K562 cells is accompanied by more than 200-fold increase in the c-sis mRNA level. We have now localized transcriptional enhancers at -8.6 kb and -9.9 kb relative to the human c-.six gene transcription start site. The enhancer at -8.6 kb increases activity of the c-sis promoter by 40-60-fold specifically in K562 cells and comaps with a DNase-I-hypersensitivity (DH) site. The enhancer at -9.9 kb increases c-sis promoter activity by 5 -10-fold in K562 cells and DH at that site accompanies phorbol-ester-induced megakaryocytic differentiation. In phorbol-ester-treated K562 cells the two enhancers may be negatively influenced by a silencer that comaps with DH at -10.7/-11 .O kb. Reporter gene analysis predicted that combined activity of the upstream enhancers and the c-sis promoter may result in 100-1000-fold higher promoter activity in phorbol-ester-treated K562 cells compared with untreated cells, which can fully explain the more than 200-fold increase in c-sis mRNA level. DH at -8.6 kb and -9.9 kb was also detected in human fibroblasts and in the carcinoma cell lines HeLa and PC3, which express, respectively, undetectable, low and high levels of c-sis mRNA. Although the individual DH sites displayed 4-10-fold enhancer activity in all these cells, they lost most of their biological activity when combined in a larger fragment.In addition we localized (part of) a new transcription unit at approximately 13 kb upstream of the c-sis transcription start site. The corresponding 0.45-kb sis upstream region (sur) transcript is constitutively expressed in all cell lines examined. The expression of the sur transcript is independent of the expression of c-sis mRNA and of the pattern of DH sites far upstream of the c-sis gene. Thus, at present, there is no indication that the upstream DH sites are involved in regulation of expression of the sur gene.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

DNase‐I‐hypersensitive sites located far upstream of the human c‐sis/PDGF‐B gene comap with transcriptional enhancers and a silencer and are preceded by (part of) a new transcription unit

Dirks

Jansen

Onnekink

et al. 1993

European Journal of Biochemistry

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“…The steady-state expression levels of the 3.5-kb c-sis transcript show considerable variation in these cells, the level being highest in PC3 cells and very low in HeLa cells. Choriocarcinoma-derived cell lines JEG-3 and JAR were chosen as a model for placental cyto- trophoblasts, which express c-sis mRNA (Goustin et al, 1985). Both cell lines lack the 3.5-kb c-sis transcript and express low levels of a 2.6-kb transcript that hybridizes with c-sis cDNA probe pSM-1.…”

Section: Differential Expression Of C-sis Mrna In a Panel Of Diverse mentioning

confidence: 99%

Localization and functional analysis of DNase‐I‐hypersensitive sites in the human c‐sis/PDGF‐B gene transcription unit and its flanking regions

Dirks

Jansen

Gerritsma

et al. 1993

European Journal of Biochemistry

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We studied the regulation of the expression of the human c-sisfPDGF-B gene in the following panel of cell lines : K562 cells, in which expression is inducible by phorbol esters ; cytotrophoblastderived cell lines JEG-3 and JAR; carcinoma-derived cell lines PC3, T24 and HeLa, which show extensive differences in c-sis mRNA content; dermal fibroblasts, which do not express the gene. We demonstrate that the wide variety of levels of c-sis mRNA in these cells is mainly determined at the transcription level. Extensive gene rearrangements or amplifications, or significant differences in the stability of the c-sis transcript could not be found. In fibroblasts and placenta cell lines, inaccessibility of the c-sis promoter, rather than the absence of transcription factors that activate it, inhibits expression of the endogenous gene. Examination of the chromatin structure of the transcription unit and immediate flanking regions revealed several cell-type-specific DNase-I-hypersensitivity (DH) sites. Functional analysis of genomic fragments harbouring one or more DH sites showed the presence of negative regulatory elements within intron 1, and of an activating element downstream of the gene. A DH site, located immediately downstream of the promoter in dermal fibroblasts, may regulate accessibility of the promoter by means of specific nucleosome phasing.

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“…Presumably, autocrine loops in normal cells are tightly controlled and occur only transiently, as a response to extcrnal stimuli or in a specific phase of development. Examples include the production of basic FGF by endothelial cells [181], and of PDGF by vascular smooth muscle cells [182 --1841, placental cytotrophoblasts [185], endothelial cells in glioblastoma tumors [57] as well as by mitogen-stimulated human fibroblasts [186]. The finding of an autoinduction of PDGF [183] in fibroblasts is interesting and may suggest the presence of a positive autocrine feedback loop in growth stimulation.…”

Section: Mechanism Of; Activation O F Growth Factor Expression In Celmentioning

confidence: 96%

Growth factors as transforming proteins

Heldin

Westermark

1989

European Journal of Biochemistry

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Coexpression of the sis and myc proto-oncogenes in developing human placenta suggests autocrine control of trophoblast growth

Cited by 306 publications

References 56 publications

DNase‐I‐hypersensitive sites located far upstream of the human c‐sis/PDGF‐B gene comap with transcriptional enhancers and a silencer and are preceded by (part of) a new transcription unit

DNase‐I‐hypersensitive sites located far upstream of the human c‐sis/PDGF‐B gene comap with transcriptional enhancers and a silencer and are preceded by (part of) a new transcription unit

Localization and functional analysis of DNase‐I‐hypersensitive sites in the human c‐sis/PDGF‐B gene transcription unit and its flanking regions

Growth factors as transforming proteins

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