Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology.
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Amphiregulin↗
Biomedical subjects
R D Beauchamp
Publications and source records attributed to R D Beauchamp.
Differential regulation by TGF-beta 1 and insulin of insulin-like growth factor binding protein-2 in IEC-6 cells.
The purposes of this study were to determine the regulation of insulin-like growth factor binding protein-2 (IGFBP-2) in IEC-6 cells by transforming growth factor-beta 1 (TGF-beta 1) and insulin and to determine whether IGFBP-2 mediated the growth-inhibitory action on the cells. Utilizing Western ligand blot analysis, we found that TGF-beta 1 at concentrations of 0.5, 1.0, and 2 ng/ml significantly increased levels of 32-kDa IGFBP in the conditioned medium (CM) of IEC-6 cells in a dose-dependent fashion and that low doses of insulin (1.0 and 5.0 microgram/ml) also increased IGFBP levels in the CM of IEC-6 cells, but a high dose of insulin (10 micrograms/ml) depressed IGFBP release in the CM. Immunoblotting has shown that the IGFBP of 32 kDa was IGFBP-2 and further confirmed the above results. IGFBP-2 mRNA levels were stimulated by TGF-beta 1 (2.0 ng/ml) and suppressed by insulin (5.0 micrograms/ml). In addition, des (1-3) IGF-I (50 ng/ml) and insulin stimulated the proliferation of IEC-6 cells. Anti-IGFBP-2 antibodies partially blocked the inhibitory role in IEC-6 cell growth evoked by des (1-3) IGF-I. These findings suggest that the upregulation of IGFBP-2 by TGF-beta 1 occurs, at least in part, at the level of mRNA, whereas the regulation by insulin appears to be at a posttranslational level, and that the TGF-beta 1-stimulated production of IGFBP may contribute to the growth-inhibitory action in intestinal epithelial cells.
Animals↗
Phorbol ester-induced alteration in the pattern of secretion and storage of chromogranin A and neurotensin in a human pancreatic carcinoid cell line.
Brief phorbol ester treatment of BON cells results in a persistent release and cellular depletion of immunoreactive chromogranin A (CGA-IR) and neurotensin (NT-IR) cell contents. The purpose of the present study was to characterize the effects of 12-O-tetradecanoyl phorbol-13-acetate (TPA) on the secretion, biosynthesis, and steady-state messenger RNA (mRNA) levels of chromogranin A (CGA) and of a coresident peptide, neurotensin, by a novel human pancreatic carcinoid cell line, called BON. Acute TPA treatment (100 nM, 1 h) of BON cells resulted in 20- and 40-fold elevations in release of CGA-IR and NT-IR, respectively; and a 70-90% depletion of CGA-IR and NT-IR cell contents. TPA treatment also increased the biosynthetic rate of CGA-IR. Steady-state mRNA levels of CGA and NT/N (neurotensin/neuromedin N) were unchanged. Cell contents of CGA-IR and NT-IR were not replenished for a period of up to 6 days; secretion of CGA-IR and NT-IR persisted. In addition, BON cells failed to release CGA in response to stimulation by ionomycin and A23187 several days after acute TPA treatment. Our data indicate that the lack of replenishment of cell contents of CGA-IR and NT-IR is not due to decreases in steady-state CGA-IR and NT-IR mRNA levels, nor is it due to a decrease in biosynthesis of CGA-IR, but it is the result of a loss in the ability of TPA-treated BON cells to store and secrete CGA-IR and NT-IR in a regulated manner. These effects of TPA are mediated through the PKC pathway.
Analysis of Variance↗
Insulin-like growth factor-II expression in carcinoma in colon cell lines: implications for autocrine actions.
BACKGROUND: In the gastrointestinal tract, insulin-like growth factor-II (IGF-II) messenger RNA (mRNA) is localized mainly in mesenchymal cells, and is more abundant in the fetus than in the adult. The purposes of this study are to characterize the gene expression of IGF-II at the mRNA and protein level in seven different epithelial cell lines derived from colon carcinomas and to determine the action of IGF-II and IGF-receptors on a colon carcinoma cell line. STUDY DESIGN: Insulin-like growth factor-II mRNAs were examined by Northern analysis; conditioned media from colon carcinoma cells were concentrated, chromatographed, and examined by a specific IGF-II radioreceptor assay. Insulin-like growth factor receptors were examined by radioligand binding assays. The mitogenic role of IGF-II was determined by a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: Multiple sizes of IGF-II mRNAs were expressed in all colon carcinoma cell lines tested (six human cell lines: HCT116, COLO 205, COLO 320 DM, LoVo, DLD-1, and HT29, and one mouse cell line: MC-26). In the conditioned media of COLO 205 and HCT116 cells, 7.5 kilodaltons IGF-II and high molecular form (IGF-II and IGF binding protein complex) were detected. Both Type I and Type II IGF receptors were present on COLO 205 cells whose growth was stimulated by IGF-II. Addition of anti-IGF-I receptor and anti-IGF-II antibody in the cell culture significantly depressed growth of the COLO 205 cell line in the presence or absence of exogenous IGF-II. CONCLUSIONS: Insulin-like growth factor-II mRNAs are expressed in human and mouse colon carcinoma cell lines, which may induce production of a significant amount of biologically active IGF-II protein. The IGF-II secreted by COLO 205 cells may stimulate cell growth in an autocrine fashion through the Type I IGF receptors.
Affinity Labels↗
Transforming growth factor-beta inhibits rat intestinal cell growth by regulating cell cycle specific gene expression.
Transforming growth factor-beta 1 (TGF-beta 1) inhibits the growth of intestinal cells, but the mechanisms involved are unknown. Using a rat intestinal crypt cell line (IEC-6), we determined the site of action in the cell cycle that TGF-beta 1 acts to suppress proliferation. We also examined the effect of TGF-beta 1 on the expression of proliferation-associated "immediate early" genes (zif268, jun-B, c-myc) during the early G1 phase and the cdc2 gene during the transition from the G1 phase to the S phase of the cell cycle. Cell cycle progression was determined by incorporation of 3H-thymidine, and gene expression was analyzed by Northern blot analysis. We found that TGF-beta 1 acts to inhibit proliferation of rat intestinal crypt cells by blocking cell cycle progression at the middle G1 phase. The genes activated during G1 can be divided into TGF-beta 1 insensitive (zif268, jun-B, and c-myc) and TGF-beta 1 sensitive (the cdc2 gene). TGF-beta 1 suppresses the induction of the cdc2 gene during the G1/S transition without inhibiting the activation of immediate early genes during the early G1 phase.
Animals↗
Characterization of a human pancreatic carcinoid in vitro: morphology, amine and peptide storage, and secretion.
The study of functioning human endocrine tumors has been hampered by a lack of suitable in vitro models. We have established the first permanent cell line of a human pancreatic carcinoid tumor (BON) in culture. BON cells grow in monolayer culture and form colonies in soft agar. Injection of BON cells into nude mice produces transplantable tumors in a dose-dependent fashion. The histology of tumors in athymic mice from injection of dispersed, cultured BON cells is similar to the original histology of the resected tumor. Significant amounts of neurotensin, pancreastatin, and serotonin (5-HT) are demonstrated in the cells by radioimmunoassay (RIA) and the presence of chromogranin A, bombesin, and 5-HT is confirmed by immunocytochemistry. Numerous round and pleomorphic dense-core neurosecretory granules are present on electron microscopy. Functional receptors for acetylcholine, 5-HT, isoproterenol, and somatostatin are present on cultured cells. BON cells possess a specific transport system for uptake of 5-HT from the medium; this uptake system may be a route for regulation of autocrine effects of 5-HT on carcinoid cells. This unique human carcinoid tumor cell line should provide the opportunity for new insight into the biology of carcinoid tumors and of specific intracellular mechanisms for secretagogue action in the release of amines and peptides.
Adult↗
Lovastatin inhibits pancreatic cancer growth regardless of RAS mutation.
Lovastatin, an inhibitor of the rate-limiting enzyme of cholesterol synthesis, inhibits growth of pancreatic cancer cells. A possible mechanism of this inhibition is that lovastatin inhibits the activity of RAS protein by depleting farnesyl (an intermediate of cholesterol synthesis). The K-ras gene is frequently mutated in pancreatic cancers and RAS protein requires farnesyl to be bound to the cell membrane and thereby activated. To investigate whether lovastatin inhibition of cell growth depends upon the presence of ras mutation, codons 12/13 and 61 of ras genes were examined by the dideoxynucleotide chain-terminating method in five pancreatic cell lines (human CAPAN2, CAV, MIA Paca2, PANCi, and hamster H2T) on which lovastatin exerted a growth-inhibitory effect. These codons play a major role in tumorigenic mutation of ras genes. Lovastatin inhibited cell growth by 99% (MIA), 97% (H2T), 78% (CAV), 41% (CAPAN2), and 23% (PANC1), respectively, when cells were treated with 2.5 micrograms/ml lovastatin for 6 days. Activating point mutations were found in codon 12 of the K-ras gene (wild type:GGT) in MIA (GTT), H2T (GAT), CAPAN2 (TGT), and PANC1 (GAT) but not in CAV. In addition, the CAV cell line did not have a mutation in either H- or N-ras genes. Lovastatin inhibited the growth of CAV cells even though this cell line did not have ras mutation, suggesting that lovastatin inhibition of pancreatic cancer cell growth is not directly dependent on the presence of ras mutation.
Animals↗
Activation of hepatic proliferation-associated transcription factors by lipopolysaccharide.
BACKGROUND: The hepatic acute-phase response is the result of reprogramming of gene expression in the liver. Similar acute-phase responses occur in regenerating liver after partial hepatectomy and are preceded by increases in the expression of a set of transcriptional regulatory proteins that are encoded by "immediate-early" genes. The purpose of this study was to determine whether acute systemic inflammation after lipopolysaccharide injection induces hepatic immediate-early genes that are induced by partial hepatectomy. METHODS: Two- to 4-month-old Balb/c mice received intraperitoneal Escherichia coli lipopolysaccharide (0111:B4; 100 micrograms), and total liver RNA, nuclear protein extracts, or total liver protein lysates were obtained at 0, 1, 3, 12, and 24 hours. RNA blot hybridization analysis was used to determine steady-state messenger RNA levels for c-jun, jun-B, jun-D, c-fos, fos-B, fra-1, nup475, and zif268. Specific nuclear protein-binding activity was determined by gel mobility shift assay. The protein c-Jun was detected by antibody-blocking experiments, and Jun-B was detected by gel supershift assay of the activating protein (AP-1) complex. Steady-state Jun-B levels were determined by immunoblot analysis. RESULTS: Intraperitoneal injection of lipopolysaccharide is followed by induction (from fivefold to 13-fold) of c-jun, jun-B, c-fos, zif268, and nup475 messenger RNAs in the liver. Lipopolysaccharide induced increases in AP-1 and Zif268 consensus DNA-binding activity in mouse liver. The proteins c-Jun and Jun-B are detected in the AP-1 complex after administration of lipopolysaccharide. CONCLUSIONS: The induction of hepatic immediate-early genes after lipopolysaccharide is similar to that that follows partial hepatectomy. These transcription factors likely have important roles in the reprogramming of gene expression that leads to the acute-phase response.
Animals↗
Novel action of transforming growth factor beta 1 in functioning human pancreatic carcinoid cells.
We have shown recently that 5-HT is an autocrine growth stimulatory factor for a cell line (BON) that is derived from a human pancreatic carcinoid tumor. This action is mediated by a 5-HT receptor-linked decrease of cyclic adenosine monophosphate (AMP) production, but not mediated by a 5-HT receptor-linked stimulation of phosphatidylinositol hydrolysis. The BON cells also express transforming growth factor betas (TGF beta s) (1, 2, and 3) and release TGF beta into their medium. In this study, we examined the effects of TGF beta on the secretion of 5-HT, on signal transduction pathways involved in 5-HT secretion, and on growth of BON cells. TGF beta 1 inhibited basal and acetylcholine-stimulated release of 5-HT, but did not inhibit isobutylmethylxanthine-stimulated release of 5-HT. TGF beta 1 inhibited both basal and acetylcholine-stimulated hydrolysis of phosphatidylinositol in a dose dependent manner, but did not affect cyclic AMP production. TGF-beta 1 inhibited growth of BON cells in culture; this effect was reversed by exogenously administered 5-HT. Three different specific and saturable TGF beta 1 binding sites were identified; binding assays performed after mild acid wash (0.1% acetic acid, pH 2.5) conditions uncovered TGF beta receptors that were apparently occupied by endogenously produced TGF beta species. Affinity cross-linking assay showed that BON cells had three different TGF beta binding proteins. These results suggest that TGF beta 1 can inhibit growth of BON cells by altering secretory responses of 5-HT by means of receptor-mediated inhibition of phosphatidylinositol hydrolysis. We conclude that growth of BON cells is regulated, at least in part, by the opposing receptor-mediated autocrine actions of 5-HT and TGF beta.
Affinity Labels↗
Insulinlike growth factor-binding protein modulates the growth response to insulinlike growth factor 1 by human gastric cancer cells.
BACKGROUND: This study determined whether the resistance to the mitogenic effect of insulinlike growth factor 1 (IGF-1) in AGS (we found that IGF-1 had almost no effect on the growth of AGS) cells is caused by the absence of IGF-1 receptor on the cells or by the interference of endogenous IGFs and IGF-binding protein (IGFBP). METHODS: IGF-1 receptors were examined by radioligand binding assay. The protein in conditioned medium and the molecular weight of IGF-1 receptors on AGS cells were determined by affinity cross-linking with 125I-IGF-1 followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Messenger RNAs for IGF-1, IGF-2, and IGFBP-4 were detected by Northern analysis. RESULTS: AGS cells possessed a single class of high-affinity binding sites for IGF-1 (dissociation constant [Kd], 0.51), with a binding capacity approximately 4 x 10(4) sites per cell. The size of the alpha subunit of IGF-1 receptors on cell membranes was approximately 130 kilodaltons. des (1-3) IGF-1, a truncated IGF-1 with very low affinity to IGFBPs, stimulated AGS cell growth in dose-dependent fashion. The medium conditioned by AGS cells contained IGFBPs of 27-32 and 37-42 kilodaltons. AGS cells expressed messenger (mRNA) RNAs for IGF-2 and IGFBP-4 but not for IGF-1, whereas another gastric carcinoma cell line (SIIA), whose growth is stimulated by IGF-1, expressed mRNA IGF-2 but did not express mRNA for IGF-1 or IGFBP-4: CONCLUSIONS: The relative absence of growth response of AGS cells to IGF-1 is due to the endogenously produced IGFBPs sequestering IGF-1 and preventing receptor interaction.
Adenocarcinoma↗
Glutamine is essential for epidermal growth factor-stimulated intestinal cell proliferation.
BACKGROUND: Glutamine stimulates growth of intestinal mucosa in vivo, but the mechanisms involved are unknown. The purpose of this study was to determine whether glutamine is essential for proliferation of enterocytes stimulated by epidermal growth factor (EGF). In addition, we determined which specific mitogenic actions of EGF require glutamine. METHODS: A nontransformed rat intestinal mucosal cell line (IEC-6) was stimulated with EGF (20 ng/ml) without and with glutamine (0.1 to 10 mmol/L). DNA, RNA, and protein synthesis were quantitated by determining incorporation of tritiated thymidine, tritiated uridine, and 14C-leucine, respectively. Cell numbers and messenger RNA levels of early growth response genes (zif268, jun-B, c-myc) were also determined. RESULTS: Glutamine was required for EGF stimulation of DNA, RNA, and protein synthesis and cell replication; however, EGF-stimulated expression of zif268, jun-B, and c-myc occurred in the absence of glutamine. CONCLUSIONS: This study showed that glutamine is essential for EGF-stimulated intestinal mucosal cell proliferation. The mitogenic effects of EGF can be divided into the glutamine-independent, such as the signal transduction pathway leading to the induction of early growth response genes, and the glutamine-dependent, including DNA, RNA, and protein synthesis.
Animals↗
Unexpected growth-stimulatory effect of somatostatin analogue on cultured human pancreatic carcinoid cells.
Therapeutic efficacy of a synthetic somatostatin analogue for the treatment of carcinoid tumors is still controversial. In vivo studies performed in our laboratory showed that a somatostatin analogue, SMS 201-995, significantly inhibited growth of human pancreatic carcinoid (BON) tumors xenotransplanted into athymic nude mice. In the present study, however, SMS 201-995 did not inhibit in vitro growth of BON cells, but rather SMS 201-995 stimulated growth in a dose-dependent fashion. The growth-stimulatory effect was likely mediated through the reduction of cyclic AMP production. Unsuccessful treatment of certain types of carcinoid tumor with SMS 201-995 may be partly due to the direct growth-stimulatory effect of SMS 201-995 on carcinoid cells.
Carcinoid Tumor↗
Receptor-mediated autocrine growth-stimulatory effect of 5-hydroxytryptamine on cultured human pancreatic carcinoid cells.
5-hydroxytryptamine (5-HT) is a mitogen for fibroblasts, vascular smooth muscle cells, renal mesangial cells, and jejunal crypt cells. The human carcinoid cell line (termed BON) that we established in our laboratory from a pancreatic carcinoid tumor produces and secretes 5-HT. In this study, therefore, we examined the effect of 5-HT on growth of BON cells. Furthermore, by use of selective 5-HT receptor antagonists, we examined receptor and post-receptor mechanisms by which 5-HT-induced responses were produced. 5-HT stimulated growth of BON cells. 5-HT stimulated phosphatidylinositol (PI) hydrolysis in a dose-dependent fashion and inhibited cyclic AMP production in a dose-dependent fashion. The 5-HT1A/1B receptor antagonist, SDZ 21-009, prevented the reduction of cyclic AMP production evoked by 5-HT and inhibited the mitogenic action of 5-HT. The 5-HT1C/2 receptor antagonist, mesulergine, competitively inhibited PI hydrolysis, but did not affect the mitogenic action of 5-HT. The mitogenic action of 5-HT and the reduction of cyclic AMP production evoked by 5-HT were also inhibited by pertussis toxin. These results suggest that 5-HT is an autocrine growth factor for BON cells and that mitogenic mechanism of 5-HT involves receptor-mediated inhibition of the production of cyclic AMP which may be linked to pertussis toxin-sensitive GTP binding protein. 8-bromo-cyclic AMP inhibited growth of BON cells whereas 8-bromo-cyclic GMP had no effect on cell growth. Involvement of protein kinase A in BON cell growth regulation was confirmed by the observation that a cAMP-dependent protein kinase antagonist (Rp-cAMPS) could stimulate BON cell growth.
8-Bromo Cyclic Adenosine Monophosphate↗
Inhibition of pancreatic adenocarcinoma cell growth by lovastatin.
RAS protein (p21 ras) requires farnesyl (an intermediate of cholesterol synthesis) for activation. Activating mutations of K-ras gene have been detected in most human pancreatic adenocarcinomas. In the present study, the effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, the rate-limiting enzyme of cholesterol synthesis, on the growth of five pancreatic cancer cell lines (human-CAV, MIA Paca2, CAPAN2 and PANC1, and hamster-H2T) in vitro and of two cell lines (CAV and H2T) in vivo was examined. Inhibition of cell growth was observed with lovastatin doses at or above 2.5 micrograms/mL for H2T, CAV, MIA Paca2, and CAPAN2 or 10 micrograms/mL in PANC1. The H2T cell line was studied further to determine the reversibility of growth inhibition. Mevalonic acid (1 mmol/L) reversed lovastatin-induced inhibition of cell growth if it was added with lovastatin (2.5 micrograms/mL). Similarly, removal of lovastatin from the medium within 24 hours after treatment allowed recovery of cell growth. The effect of lovastatin on cell growth was irreversible after 48 hours of exposure. The survival fraction of H2T cells was markedly decreased by 1- or 24-hour exposure to 75 micrograms/mL but not to doses ranging from 0.5 to 60 micrograms/mL of lovastatin. Growth of pancreatic carcinoma xenografts (CAV and H2T) in nude mice was inhibited by a subcutaneous infusion of lovastatin (50 micrograms/h). These results indicate that mevalonic acid or a metabolite in the cholesterol synthesis pathway is necessary for growth of pancreatic cancer cells and suggest that lovastatin should be further examined as a potential therapeutic agent for pancreatic cancer.
Animals↗
Increased production of transforming growth factor alpha following acute gastric injury.
Transforming growth factor alpha (TGF-alpha) production recently has been found in normal mammalian gastric mucosa. Inasmuch as TGF-alpha and epidermal growth factor (EGF) both stimulate epithelial cell migration and proliferation and suppress gastric acid secretion, the authors of the current study proposed that these growth factors may participate in tissue repair after acute gastric mucosal injury. Consequently, TGF-alpha and EGF production were examined after orogastric administration of either acidified taurocholate or 0.6 mol/L HCl to rats. TGF-alpha messenger RNA (mRNA) expression increased in a dose- and time-dependent manner after administration of taurocholate, whereas EGF mRNA expression was not detected. Radioimmunoassay of gastric mucosal scrapings obtained 6 hours after gastric injury induced by 0.6 mol/L HCl showed a 2.1-fold increase in immunoreactive TGF-alpha but no increase in immunoreactive EGF. In addition, there was a 68-fold increase in immunoreactive TGF-alpha in gastric juice within 30 minutes of gastric instillation of HCl and, again, no increase in immunoreactive EGF. There is a rapid appearance of TGF-alpha in the gastric juice within 30 minutes of injury, which is followed by increased expression of TGF-alpha mRNA and protein in the gastric mucosa. These studies suggest that locally produced TGF-alpha may participate in gastric mucosal repair following acute gastric injury to rats.
Animals↗
The role of endogenous prostaglandins in hormone-stimulated pancreatic exocrine secretion.
The authors have previously shown that neurotensin and secretin inhibit gastric acid secretion in the dog and that these actions are inhibited by the prostaglandin synthesis inhibitor indomethacin. Conversely, neurotensin and secretin share similar stimulatory effects on pancreatic exocrine secretion. In the present study, the effects of blockade of prostaglandin synthesis by indomethacin on neurotensin-, cholecystokinin-, and secretin-stimulated exocrine secretion are examined along with the effects of these same agents on the release of pancreatic polypeptide. The studies were performed on conscious dogs with chronic gastric and pancreatic cannulas. Dose-dependent increases in pancreatic exocrine secretion of water and bicarbonate were observed with IV infusion of neurotensin or secretin; however, inhibition of prostaglandin synthesis by indomethacin abolished this response. Protein secretion stimulated by either neurotensin or cholecystokinin was not affected by prostaglandin inhibition. Cholecystokinin and neurotensin infusion stimulated release of pancreatic polypeptide; only neurotensin-stimulated release of pancreatic polypeptide was inhibited by indomethacin treatment. It is concluded that intact prostaglandin synthesis is necessary for the actions of neurotensin and secretin (but not that of cholecystokinin) on pancreatic exocrine secretion of water and bicarbonate and for neurotensin- (but not cholecystokinin-) stimulated release of pancreatic polypeptide.
Animals↗
Transforming growth factor (TGF)-beta stimulates hepatic jun-B and fos-B proto-oncogenes and decreases albumin mRNA.
Transforming growth factor-beta (TGF-beta) modulates some components of the acute phase response in hepatic cells. The mechanisms for these actions of TGF-beta are largely unknown. The authors recently found that the decrease in albumin mRNA after TGF-beta 1 treatment required de novo RNA and protein synthesis, suggesting that TGF-beta acts through induction of another gene. The purpose of the current study was to determine whether TGF-beta 1 could regulate the expression of both the jun and fos genes that encode transcriptional regulatory proteins that constitute the AP-1 complex, and to determine whether expression of these genes may be coordinated with the decrease in albumin mRNA. Northern blot hybridization was used to determine levels of specific mRNAs. Transforming growth factor-beta 1 increased the levels of both jun-B and fos-B mRNA by 60 minutes after treatment of mouse hepatoma (BWTG3) cells. When TGF-beta 1 was removed from the media after 4 hours, there was a sustained effect of increased jun-B and decreased albumin mRNA (greater than 48 hours), and the subsequent decrease in jun-B levels coincided with the increase in albumin mRNA. The tumor-promoting phorbol ester (phorbol 12-myristate 13-acetate [PMA]), known to induce jun and fos gene expression, caused increases in jun-B and fos-B that preceded the decrease in albumin mRNA levels at 24 hours. These observations are consistent with our hypothesis that jun-B and fos-B induction may participate in downregulation of albumin synthesis as well as other hepatic responses to TGF-beta.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Transforming growth factor-beta (TGF-beta 1) inhibits pancreatic acinar cell growth.
Effects of transforming growth factor (TGF)-beta 1 on mouse pancreatic acinar cell growth and rapid intracellular responses to cholecystokinin (CCK) were examined in vitro. TGF-beta 1 inhibited [3H]thymidine incorporation stimulated by either the CCK analogue caerulein, epidermal growth factor, or insulin. TGF-beta 1 inhibition of growth stimulated by a maximal dose of caerulein (1 nM) was dose dependent with one-half maximal effects occurring at approximately 5 pM and maximal inhibition seen with 30 pM. In contrast to its effects on CCK-stimulated [3H]thymidine incorporation, TGF-beta 1 had no effect on CCK-stimulated increases in amylase release or intracellular Ca2+ concentration. To determine whether TGF-beta 1 might be an autocrine growth regulator, pancreatic mRNA was probed for the presence of TGF-beta 1 transcripts. TGF-beta 1 mRNA was not detected in whole pancreas but was detectable with increasing abundance over time in primary cultures of pancreatic acinar cells. The appearance of the TGF-beta 1 mRNA corresponded to the period of rapid cellular proliferation in vitro. These results suggest that TGF-beta 1 may be an autocrine growth inhibitor in the pancreas and that the inhibitory effects of TGF-beta 1 on pancreatic acinar cell growth occur at sites distal to those involved in stimulus-secretion coupling.
Animals↗