Regulation of intestinal epithelial cell growth by transforming growth factor type beta.

Barnard, J. A.; Beauchamp, R. Daniel; Coffey, Robert J.; Moses, Harold L.

doi:10.1073/pnas.86.5.1578

Cited by 294 publications

(177 citation statements)

References 41 publications

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“…TGF-b1 appears to be an important physiological a ector of intestinal epithelial regeneration and di erentiation (Kurokowa et al, 1987;Barnard et al, 1989;Ko et al, 1994). Furthermore, establishment of a link between TGFb1 and cyclin D1 provides an important clue into the etiology of epithelial neoplasia in the gut.…”

Section: Discussionmentioning

confidence: 99%

“…One such signal consists of an autocrine/paracrine regulatory loop that involves transforming growth factor-beta 1 (TGF-b1). Enterocytes begin to synthesize TGF-b1 soon after they migrate from the intestinal crypts (Barnard et al, 1989(Barnard et al, , 1993. The hormone is secreted in an inactive form and is activated in the extracellular milieu.…”

Section: Introductionmentioning

confidence: 99%

“…Mid-log phase cultures of either cell line cease to proliferate when exposed to TGF-b1 (Barnard et al, 1989;Ko et al, 1994Ko et al, , 1995. TGF-b1-treated intestinal epithelial cells arrest with a G1 DNA content; and TGF-b1 blocks DNA synthesis that normally occurs when serumstarved, quiescent cells are stimulated by the addition of serum growth factors (Ko et al, , 1995.…”

Section: Introductionmentioning

confidence: 99%

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TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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Transforming growth factor-beta 1 (TGF-b1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-b1-mediated cell cycle arrest. TGF-b1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGFb1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no e ect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-b1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-b1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-b1-mediated arrest of intestinal epithelial cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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“…It has been observed before that this factor can be chemoattractant on human peripheral blood monocytes 21 and that it is also able to induce migratory gut-seeking lymphocytes to become resident within the intraepithelial compartment of the gut. 22,23 It is also possible that the accumulation of apoptotic cells that would result from the activity of the transgene on secretory hyperplastic lesions could attract mononuclear cells to the area.…”

Section: Weak Wap-tgf␤1 Tumor Inhibitory Effect May Be a Consequence mentioning

confidence: 99%

Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

et al. 2001

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It has previously been shown that transgenic female mice expressing TGF␤1 under control of regulatory elements of the whey-acidic protein (WAP) gene were unable to lactate. This was due to the increased apoptosis of the cells committed to the lobular-lactogenic phenotype. Our goal was to determine whether the expression of WAP-TGF␤1 transgene could inhibit MMTV (mouse mammary tumor virus) tumorigenic activity in the mammary gland. It is well known that the infection with this virus produces focal hyperplastic secretory nodules (HANs) and, some variants can also induce ductal pregnancy-dependent lesions (plaques). In either case, MMTV infection leads ultimately to the appearance of malignant mammary tumors. The results shown herein demonstrate that TGF␤1 expression in the secretory mammary epithelium does not suppress mammary tumorigenesis in MMTV infected mice. Although MMTV infected WAP-TGF␤1 transgenic females displayed a strong impairment of lobule-alveolar development, carcinogenesis induced by any of the four MMTV variants used herein proceeded unabated. WAP-TGF␤1 tumors that showed a strong expression at the WAP promoter, appeared later and grew more slowly than their wild-type counterparts. Transgenic females also had a lower incidence of HANs and plaques. Our study suggests that the epithelial target cells for tumorigenic mutations are probably progenitor cells that are not susceptible to the apoptotic effect of TGF␤1. Alternatively, their daughters cells that display the secretory phenotype and could be more involved in the formation of premalignant lesions continue to die due to the expression of the transgene. © 2001 Wiley-Liss, Inc. Key words: mammary tumor; MMTV; TGF␤1; stem cellsTransforming growth factor-␤1 is a member of a large superfamily of polypeptides and seems to affect many key events in normal growth and differentiation. 1,2 There is good evidence that members of the TGF␤1 gene family may indeed contribute essential signals for the development and secretory maturation of the mammary epithelium. An approach to TGF␤ function and mammary gland development has been the use of transgenic mice. TGF␤1 has been targeted to the mammary epithelium from different transcriptional promoters in two transgenic mouse models. In one, the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) was used to promote expression of TGF␤1 in mammary epithelium. 3 In this biological model, a transient but distinct inhibition of mammary ductal extension and side branching was observed between 3 and 6 weeks of age; however subsequent development during pregnancy and lactation proceeded apparently unperturbed. In the second transgenic mouse model, TGF␤1 was expressed under the control of the whey acidic protein (WAP) promoter. This promoter is mammary epithelium-specific and most active during late pregnancy and lactation. In this model no inhibition of mammary ductal growth at puberty was observed. 4 With the onset of pregnancy, lobule-alveolar growth and development were impaired to the extent that lactation was...

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“…TGF-b is a potent inhibitor of intestinal crypt cell proliferation (Kurokowa et al, 1987;Barnard et al, 1989). This inhibition of cultured intestinal cell proliferation after TGF-b treatment is the result of mid-to-late G1 cell cycle arrest associated with downregulation of cyclin D1 (Ko et al, 1995) and inhibition of Cdk4-associated Rb kinase activity (Ko et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

et al. 1999

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The precise role of TGF-b in colorectal carcinogenesis is not clear. The purpose of this study was to determine the phenotypic alterations caused by chronic exposure to TGF-b in non-transformed intestinal epithelial (RIE-1) cells. Growth of RIE-1 cells was inhibited by 475% following TGF-b1 treatment for 7 days, after which the cells resumed a normal growth despite the presence of TGF-b1. These`TGF-b-resistant' cells (RIE-Tr) were continuously exposed to TGF-b for 450 days. Unlike the parental RIE cells, RIE-Tr cells lost contact inhibition, formed foci in culture, grew in soft agarose. RIE-Tr cells demonstrated TGF-b-dependent invasive potential in an in vitro assay and were resistant to Matrigel and Na-butyrate-induced apoptosis. The RIETr cells were also tumorigenic in nude mice. The transformed phenotype of RIE-Tr cells was associated with a 95% decrease in the level of the type II TGF-b receptor (TbRII) protein, a 40-fold increase in cyclooxygenase-2 (COX-2) protein, and 5.9-fold increase in the production of prostacyclin. Most RIE-Tr subclones that expressed low levels of TbRII and high levels of COX-2 were tumorigenic. Those subclones that express abundant TbRII and low levels of COX-2 were not tumorigenic in nude mice. A selective COX-2 inhibitor inhibited RIE-Tr cell growth in culture and tumor growth in nude mice. The reduced expression of TbRII, increased expression of COX-2, and the ability to form colonies in Matrigel were all reversible upon withdrawal of exogenous TGFb1 for the RIE-Tr cells.

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Regulation of intestinal epithelial cell growth by transforming growth factor type beta.

Abstract: A nontransformed rat jejunal crypt cell line (IEC-6) expresses transforming growth factor type 131 (TGFIll) mRNA, secretes latent 125I-labeled TGF-j31 competing activity into culture medium, and binds '2SI-labeled TGF-P1 to specific, high-affimity (Kd = 3.7 pM) cell surface receptors.

Cited by 294 publications

References 41 publications

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Impairment of mammary lobular development induced by expression of TGF?1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

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