Effects of growth factors on an intestinal epithelial cell line: Transforming growth factor β inhibits proliferation and stimulates differentiation

Kurokowa, Misuzu; Lynch, Kathy E.; Podolsky, Daniel K.

doi:10.1016/0006-291x(87)91481-1

Cited by 294 publications

(144 citation statements)

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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%

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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%

“…The hormone is secreted in an inactive form and is activated in the extracellular milieu. Activated TGFb1 inhibits enterocyte proliferation and stimulates di erentiation and migration of these epithelial cells (Kurokowa et al, 1987;Ciacci et al, 1993;Ko et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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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“…The associated presence of receptors for these ligands on some ofthe same cell lines suggests that these peptides may provide autocrine regulation ofgrowth in these cells. Preliminary studies in this laboratory using the nontransformed IEC-6 line derived from the rat small intestine found that TGF ,3 can be a potent growth inhibitor in this system and can promote expression ofat least some features of the differentiated villus cell (2,16). In this report, we demonstrate that TGF a and 13 are indeed present in intestinal epithelial cells but are differentially produced within the crypt-tovillus continuum.…”

Section: Tems (I5)mentioning

confidence: 99%

“…The maintenance of mucosal integrity in the face of constant and rapid turnover of these cell populations suggests that exquisite mechanisms must exist to balance proliferative activity with both commitment to differentiation and loss of mature cells from the villus. A number of observations in both primary cells and established cell lines derived from the intestinal epithelium and human colon carcinomas indicate that soluble peptide growth factors may be essential in regulating proliferative activity in intestinal epithelial cells (1)(2)(3)(4)(5). A number of investigators have speculated that epidermal growth factor may play an important role in view of the detection of epidermal growth factor (EGF)' receptors on enterocytes (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of transforming growth factors alpha and beta in rat intestinal epithelial cells.

Koyama¹,

Podolsky

1989

J. Clin. Invest.

216

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Expression of transforming growth factor a (TGF a), and transforming growth factor 13 In addition to the transcripts identified in the primary intestinal cells, this cell line contained an additional larger TGF a transcript (4.8 kb) and smaller TGF 13 transcripts (2.2 and 1.8 kb). TGF a and TGF 13 may play a significant role in the regulation of the balance between proliferative and differentiated cell compartments in the intestinal epithelium through both autocrine and paracrine mechanisms. IntroductionThe intestinal mucosa is composed of a highly dynamic epithelial cell population in which proliferating cells are spatially segregated in the crypt from a gradient of increasingly differentiated cells present along the longitudinal axis of the villus. The maintenance of mucosal integrity in the face of constant and rapid turnover of these cell populations suggests that exquisite mechanisms must exist to balance proliferative activity

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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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Effects of growth factors on an intestinal epithelial cell line: Transforming growth factor β inhibits proliferation and stimulates differentiation

Cited by 294 publications

References 14 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

Differential expression of transforming growth factors alpha and beta in rat intestinal epithelial cells.

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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