Type beta transforming growth factor/growth inhibitor stimulates entry of monolayer cultures of AKR-2B cells into S phase after a prolonged prereplicative interval.

317

113

Various oncogenes or epidermal growth factor (EGF) induce transcription of a 1.9-kilobase RNA (transin RNA) in rat fibroblasts. The induction by EGF can be blocked by cycloheximide. Thus the response of the transin gene to EGF appears to require de novo protein synthesis. Transin RNA induction is specific to EGF, as neither insulin, platelet-derived growth factor, fibroblast growth factor, nor transforming growth factor P could elicit the same response. However, transforming growth factor 3 could block the EGF induction of transin RNA. Whereas the calcium ionophore A23187 and the tumor promoter TPA, either alone or administered together, did not increase transin RNA levels, TPA could synergise with a serum factor to effect such an increase. Dibutyryl cyclic AMP also induced transin RNA. Treatment of cells with the microfilamentdisrupting agent cytochalasin B, but not the microtubule-disrupting agent colcemid, resulted in an increase in transin RNA levels, suggesting a role for the cytoskeleton in control of transin gene expression. The transin RNA does not contain repeated sequences and appears to be encoded by a single-copy gene. The protein sequence encoded by the last four exons of the transin gene shows some homology to two regions of the heme-binding protein hemopexin.Detailed knowledge of the mechanisms of action of oncogenes, growth factors, and growth factor receptors is important as a means of furthering our understanding of the loss of growth control characteristic of the neoplastic state. The recent discoveries of structural and functional similarities between certain oncogene products and growth factors or growth factor receptors has opened avenues of research that continually reveal new links between the action of oncogenes and growth factors (9, 21). Thus the recent finding that the c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor colony stimulating factor (CSF-1) (49) joins the previous observations that the cellular homolog of the oncogene v-sis is a gene encoding platelet-derived growth factor (PDGF; 12, 59) and that the product of the retroviral oncogene v-erbB appears to be a truncated version of the cellular epidermal growth factor (EGF) receptor, lacking the EGF binding domain (13). While these findings show that some oncogenes may function by imitating growth factors or occupied growth factor receptors, little is known about how the growth factor/receptor interaction itself leads to accomplishment of the complex events involved in cell division.One of the most studied growth factor/receptor systems is the interaction between EGF and its receptor at the cell surface. This interaction activates the receptor's tyrosine kinase activity (58) and leads to a rapid increase in intracellular calcium levels and pH (22,36). Another consequence of EGF treatment of a variety of cell types is a rapid increase in levels of c-myc, c-fos, and actin mRNAs (8,15,33,37). This increase, a result either of a decreased rate of mRNA degradation (c-myc; 7) or an i...

Section: Discussionmentioning

confidence: 99%

Isolation of the oncogene and epidermal growth factor-induced transin gene: complex control in rat fibroblasts.

Lm¹,

Leroy²,

Ruhlmann³

et al. 1986

317

113

“…TGF, induces the growth of AKR-2B mouse fibroblasts in soft agar and, to some extent, the agar growth of NRK-49F rat kidney cells (55). TGFP stimulation of DNA synthesis in AKR-2B cells occurs after a prolonged prereplicative phase when compared with stimulation by other growth factors, such as EGF, platelet-derived growth factor (PDGF), and FGF (62). In fact, TGF3 induces the expression of other mitogens, such as both polypeptide chains of PDGF (34,38).…”

mentioning

confidence: 99%

Enhanced jun gene expression is an early genomic response to transforming growth factor beta stimulation.

Pertovaara¹,

Sistonen²,

Bos³

et al. 1989

213

Transforming growth factor 0 (TGFP) is a multifunctional polypeptide that regulates proliferation, differentiation, and other functions of many cell types. The pathway of TGFI8 signal transduction in cells is unknown. We report here that an early effect of TGFOI is an enhancement of the expression of two genes encoding serum-and phorbol ester tumor promoter-regulated transcription factors: the junB gene and the c-jun proto-oncogene, respectively. This stimulation was observed in human lung adenoc'arcinoma A549 cells which were growth inhibited by TGFj, AKR-2B mouse embryo fibroblasts which were growth stimulated by TGFI, and K562 human erythroleukemia cells, which were not appreciably affected in their growth by TGFI.

“…The specific effect of TGF-1l depends on many variables, including cell type and the presence of other growth factors (7,16,49,58). Potent effects are particularly evident in blood cells; TGF-131 regulates monocyte chemotaxis and inhibits T-cell, B-cell, and NK cell function (26,27,50,65).…”

mentioning

confidence: 99%

A phorbol ester-regulated ribonuclease system controlling transforming growth factor beta 1 gene expression in hematopoietic cells.

Wager¹,

Assoian²

1990

12-Tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of U937 promonocytes leads to a 30-fold increase in transforming growth factor ,Bl (TGF-,1l) gene expression, and this effect results from a stabilized mRNA. Similar up-regulation was detected in TPA-treated K562 erythroblasts but was absent from cell lines that do not differentiate in response to TPA. Related studies in vitro showed that postnuclear extracts of U937 promonocytes contain a ribonuclease system that degrades TGF-11 mRNA selectively and that this system is completely blocked by prior treatment of the cells with TPA. These data identify a new mechanism for regulating TGF-pl mRNA levels and allow us to establish the overall basis for control of TGF-,B1 gene expression by activation of protein kinase C. Our results also provide a new basis for understanding the long-term up-regulation of TGF-,Bl gene expression that can accompany hematopoietic cell differentiation.Transforming growth factor 13 (TGF-,11) has widespread and complex effects on cells, including both stimulation and inhibition of growth and differentiation (37,42,61,63). The specific effect of TGF-1l depends on many variables, including cell type and the presence of other growth factors (7,16,49,58). Potent effects are particularly evident in blood cells; TGF-131 regulates monocyte chemotaxis and inhibits T-cell, B-cell, and NK cell function (26,27,50,65). Several differentiated hematopoietic cell types (6,19,26,27) express relatively high levels of TGF-,1l mRNA, suggesting the potential for autocrine and paracrine effects of the growth factor on blood cell physiology and pathology.The pervasive effects of TGF-131 emphasize the need to understand mechanisms that regulate expression of this protein. Several studies have shown that biosynthesis of TGF-p1 can be regulated by controls on transcription (28-30, 33, 56). Two active promoters have been characterized in the human by transfection studies with chimeric chloramphenicol acetyltransferase constructs and by structural analysis of TGF-131 mRNAs. Enhancer domains for several established transcription factors have also been identified in these promoter regions. Phorbol esterresponsive elements (TREs) have been identified in both the upstream and downstream domains of the TGF-13 gene. The existence of these TREs explains, at least in part, the observation that activators of protein kinase C such as 12-tetradecanoylphorbol-13-acetate (TPA) and platelet-derived growth factor stimulate expression of TGF-,11 mRNA in target cells (1,56,64). TGF-131 stimulates transcription of its own gene, and the cis-acting sequences mediating this effect appear to coincide with upstream TREs (28).The importance of transcriptional regulation notwithstanding, many studies have described clear examples in which posttranscriptional controls play major roles in determining overall gene expression (13,14). For example, his-* Corresponding author.tone mRNAs are selectively stabilized in S phase of the cell cycle (18, 60), transcripts encoding colony-sti...