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At least 991 records · Page 55Linked to original sources
PubMed1996

Expression of autocrine motility factor receptor correlates with disease progression in human gastric cancer.

Up-regulation of autocrine motility factor receptor (AMF-R) expression has been shown to be associated with invasion and metastasis of experimental tumour systems and human neoplasms. Monoclonal antibodies against AMF-R (gp78) were used to stain 221 primary gastric cancer specimens, and level of expression was examined in relation to pathological stage and prognostic values. In 125 out of 221 (56.6%) patients, gp78 was detected. Expression of gp78 was associated with macroscopic type, lymphatic and venous invasions, and lymph node and peritoneal metastasis. The level of gp78 expression in the cancer specimens was associated with histopathological stage and grade of tumour penetration. Positive gp78 expression was significantly associated with poor prognosis (P < 0.001). This significant relationship remained among patients in stage II and III. The results suggest that gp78 expression could be used as a prognostic marker in gastric cancer patients.

Adenocarcinoma↗
PubMed2000

Autocrine growth regulation of CD30 ligand in CD30-expressing Reed-Sternberg cells: distinction between Hodgkin's disease and anaplastic large cell lymphoma.

Persistent expression of high levels of CD30 in Hodgkin's Reed-Sternberg (H-RS) cells and anaplastic large-cell lymphoma (ALCL) cells, but not in most T- or B-cell lymphomas, suggests the presence of an underlying mechanism leading to the abnormality and possible involvement of CD30 in the growth and survival of these two unique types of tumors. In this study, we examined the effect of CD30 ligand (CD30L) on CD30-positive H-RS and ALCL cells in long-term cultures or in primary cultures. CD30L induced various degrees of proliferation in three long-term cultured H-RS cell lines (L428, HDLM-2, and KM-H2) as well as in primary cultures of H-RS cells obtained directly from patients with Hodgkin's disease. In contrast, significant inhibition was observed in one of the ALCL cell lines (SU-DHL-1), but no growth inhibition or promotion in responding to exogenous CD30L was detected in three others (PB-1, JB-6, and McG-2), nor in primary cultures of ALCL cells. Expression of CD30L was determined by polymerase chain reaction in long-term cultured cells and by an immunohistochemical method in H-RS or ALCL cells de novo in tissue sections. None of the H-RS and ALCL cell lines was positive for CD30L. In tissue sections, we noticed that ALCL cells were generally CD30L-negative. In contrast, the anti-CD30L antibody reacted with a majority of H-RS cells with diffuse cytoplasmic staining. Most H-RS cells were CD30-positive, indicating co-expression of CD30 and CD30L in the majority of lymphoma cells. The persistent high levels of CD30 and CD30L expression in H-RS cells suggest that the autocrine CD30L-CD30 cytokine-receptor loop, in addition to having the paracrine activity previously thought to exist, could play important roles in the proliferation of H-RS cells. In contrast, the CD30L-mediated cytotoxicity may participate in the regression or slow progression of ALCL during the early phase of the disease in selected patients. However, when the disease progresses, the ALCL cells are likely to become resistant to exogenous CD30L.

Animals↗
PubMed2001

Co-expression of VEGF-C and its receptors, VEGFR-2 and VEGFR-3, in endothelial cells of lymphangioma. Implication in autocrine or paracrine regulation of lymphangioma.

Lymphangioma has long been thought of as congenital malformations resulting from the failure of lymphatic vessels communicating with the venous system in the fetal period. Alternatively, it is proposed to be true neoplasm originated from the transformation of lymphatic endothelia. To extend the molecular basis of the pathogenesis of lymphangioma, we have characterized the expression of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) in 29 cases of lymphangioma by RNA in situ hybridization. Endothelial cells of lymphangioma co-express transcripts of VEGF-C and its receptors VEGFR-3 (Flt4) and VEGFR-2 (Flk1), which are not detectable in the adjacent connective tissue. In contrast, there is little or no expression of VEGF-C, VEGFR-3, and VEGFR-2 mRNA in endothelial cells of hemangiomas, angiosarcomas, or normal lymphatic vessels of the small or large intestines. The results suggest that VEGF-C and its receptors may take active parts in the formation of lymphangioma by autocrine or paracrine regulation.

Adolescent↗
PubMed2002

VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism.

Vascular endothelial growth factor (VEGF) is a principal regulator of blood vessel formation and haematopoiesis, but the mechanisms by which VEGF differentially regulates these processes have been elusive. Here we describe a regulatory loop by which VEGF controls survival of haematopoietic stem cells (HSCs). We observed a reduction in survival, colony formation and in vivo repopulation rates of HSCs after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of HSCs, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering a soluble VEGFR-1, which acts extracellularly, induced only minor effects. These findings support the involvement in HSC survival of a VEGF-dependent internal autocrine loop mechanism (that is, the mechanism is resistant to inhibitors that fail to penetrate the intracellular compartment). Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient HSCs, revealing a function for VEGFR-1 signalling during haematopoiesis.

Animals↗
PubMed2005

Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.

Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that transmits signals through a family of G-protein-coupled receptors to control cellular differentiation and survival, as well as the vital functions of several types of immune cell. In this Review article, we discuss recent results that indicate that S1P and its receptors are required for the emigration of thymocytes from the thymus, the trafficking of lymphocytes in secondary lymphoid organs and the migration of B cells into splenic follicles. In an autocrine manner, through interactions with different G-protein-coupled receptors, S1P also enhances optimal mast-cell migration and release of pro-inflammatory mediators in allergic reactions. S1P-S1P-receptor regulatory systems might therefore be novel targets for the therapy of diverse immunological diseases.

Animals↗
PubMed2006

Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma.

Nerve growth factor (NGF) is overexpressed not only in nervous system, but also in several types of cancers. However, the role of NGF in oesophageal squamous cell carcinoma (OESCC) remains unclear. Here, we show the first evidence of NGF-TrkA autocrine loop and clinical significance of NGF overexpression in OESCC. Immunohistochemical study of 109 OESCC specimens revealed that NGF overexpression, found in 63 out of 109 patients (57.8%), was associated with lymph node metastasis, distant metastasis, higher TNM stage, poorer tumour differentiation, and poorer survival. NGF overexpression was also associated with strong expression of TrkA and negative expression of low-affinity neurotrophin receptor (p75NTR). Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) of 19 surgical specimens showed upregulation of NGF mRNA in 17 out of 19 (89%) patients. All five OESCC cell lines tested in vitro secreted detectable NGF in enzyme-linked immunosorbent assay, and expressed TrkA and p75NTR on RT-PCR and Western blot. The motility of HSA/c, one of the OESCC cell lines overexpressing NGF, was significantly decreased by either neutralising anti-NGF antibody, an inhibitor of TrkA, or NGF-small interfering RNA in transwell migration assay. Our findings suggest that NGF is of potential interest not only as a prognostic factor, but also as a novel therapeutic target in OESCC.

Adult↗
PubMed1999

Amphiregulin acts as an autocrine growth factor in two human polarizing colon cancer lines that exhibit domain selective EGF receptor mitogenesis.

Colonic enterocytes, like many epithelial cells in vivo, are polarized with functionally distinct apical and basolateral membrane domains. The aims of this study were to characterize the endogenous epidermal growth factor (EGF)-like ligands expressed in two polarizing colon cancer cell lines, HCA-7 Colony 29 (HCA-7) and Caco-2, and to examine the effects of cell polarity on EGF receptor-mediated mitogenesis. HCA-7 and Caco-2 cells were grown on plastic, or as a polarized monolayer on Transwell filters. Cell proliferation was measured by 3H-thymidine incorporation and EGF receptor (EGFR) binding was assessed by Scatchard analysis. EGFR ligand expression was determined by Northern blot analysis, reverse transcription polymerase chain reaction, metabolic labelling and confocal microscopy. We found that amphiregulin (AR) was the most abundant EGFR ligand expressed in HCA-7 and Caco-2 cells. AR was localized to the basolateral surface and detected in basolateral-conditioned medium. Basolateral administration of neutralizing AR antibodies significantly reduced basal DNA replication. A single class of high-affinity EGFRs was detected in the basolateral compartment, whereas the apical compartment of polarized cells, and cells cultured on plastic, displayed two classes of receptor affinity. Basolateral administration of transforming growth factor alpha (TGF-alpha) or an EGFR neutralizing antibody also resulted in a dose-dependent stimulation or attenuation, respectively, of DNA replication. However, no mitogenic response was observed when these agents were added to the apical compartment or to confluent cells cultured on plastic. We conclude that amphiregulin acts as an autocrine growth factor in HCA-7 and Caco-2 cells, and EGFR ligand-induced proliferation is influenced by cellular polarity.

Amphiregulin↗
PubMed2004

Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding.

Although exposure of cells to extreme hypotonic stress appears to be a purely experimental set up, it has found an application in clinical routine. For years, surgeons have washed the abdominal cavity with distilled water to lyse isolated cancer cells left after surgery. No data are available supporting this practice or evaluating the potential mechanisms of cell injury under these circumstances. Recent evidence indicates that increases in cell volume stimulate release of adenosine triphosphate and autocrine stimulation of purinergic (P2) receptors in the plasma membrane of certain epithelial cell types. Under physiological conditions, purigenic stimulation can contribute to cell volume recovery through activation of solute efflux. In addition, adenosine triphosphate-P2 receptor binding might trigger other mechanisms affecting cell viability after profound hypotonic stress. This study demonstrates a novel pathway of cell death by apoptosis in human colon cancer cells following a short hypotonic stress. This pathway is induced by transitory cell swelling which leads to extracellular release of adenosine triphosphate (ATP) and specific binding of ATP to P2 receptors (probably P2X7). Extracellular ATP induced activation of caspases 3 and 8, annexin V, release of cytochrome c, and eventually cell death. The effect of ATP can be blocked by addition of (i) apyrase to hydrolyse extracellular ATP and (ii) suramin, a P2 receptor antagonist. Finally, (iii) gadolinium pretreatment, a blocker of ATP release, reduces sensitivity of the cells to hypotonic stress. The adenosine triphosphate-P2 receptor cell death pathway suggests that autocrine/paracrine signaling may contribute to regulation of viability in certain cancer cells disclosed with this pathway.

Adenosine Triphosphate↗
PubMed2002

Autocrine costimulation: tumor-specific CD28-mediated costimulation of T cells by in situ production of a bifunctional B7-anti-CEA diabody fusion protein.

T cells require two distinct signals for optimal activation, an antigen-specific signal, provided by engagement of the T-cell receptor (TCR) and a second costimulatory signal mediated by engagement of CD28 with members of the B7 family. Although infiltrating T cells are present in many malignancies, they appear to be mostly anergic and do not attack the tumor, presumably because of the absence of activation and/or costimulatory signals. Here we describe a novel strategy for the in situ activation of tumor-specific T cells. We genetically modified T cells to secrete a bifunctional fusion protein, comprising the extracellular portion of B7-1 fused to an anticarcinoembryonic antigen (CEA) diabody. In coculture with CEA(+) tumor cells autocrine and paracrine secretion of B7-alphaCEA provided a potent tumor-specific costimulatory signal to T cells in combination with a recombinant alphaCEAxalphaCD3 bispecific diabody. B7-alphaCEA was also found to strongly enhance survival and tumor-specific activation of T cells expressing an anti-CEA TCRzeta-based chimeric immune receptor (CIR) both when expressed in cis by the T cells themselves as well as in trans, when added to the culture medium. In the absence of costimulatory signals provided by the tumor, our strategy allows T cells to "arm themselves" by the production of tumor-specific costimulatory proteins. Sustained in situ production of such molecules, like the B7-diabody fusion protein may create a favorable local environment for the activation and proliferation of tumor-reactive T cells and increase the tumoricidal activity of immunotherapeutic approaches targeting the TCR pathway.

Autocrine Communication↗
PubMed2005

TAF4 inactivation in embryonic fibroblasts activates TGF beta signalling and autocrine growth.

We have inactivated transcription factor TFIID subunit TBP-associated factor 4 (TAF4) in mouse embryonic fibroblasts. Mutant taf4(-/-) cells are viable and contain intact TFIID comprising the related TAF4b showing that TAF4 is not an essential protein. TAF4 inactivation deregulates more than 1000 genes indicating that TFIID complexes containing TAF4 and TAF4b have distinct target gene specificities. However, taf4(-/-) cell lines have altered morphology and exhibit serum-independent autocrine growth correlated with the induced expression of several secreted mitotic factors and activators of the transforming growth factor beta signalling pathway. In addition to TAF4 inactivation, many of these genes can also be induced by overexpression of TAF4b. A competitive equilibrium between TAF4 and TAF4b therefore regulates expression of genes controlling cell proliferation. We have further identified a set of genes that are regulated both by TAF4 and upon adaptation to serum starvation and which may be important downstream mediators of serum-independent growth. Our study also shows that TAF4 is an essential cofactor for activation by the retinoic acid receptor and CREB, but not for Sp1 and the vitamin D3 receptor.

Animals↗
PubMed2006

Autocrine class 3 semaphorin system regulates slit diaphragm proteins and podocyte survival.

Class 3 semaphorins are guidance proteins that play crucial roles during development. Semaphorins 3A (sema 3A) and 3F are expressed by podocytes in vivo throughout ontogeny and their function is unknown. Here we examined the expression of class 3 semaphorins (3A, 3B, 3C, 3D, 3E, and 3F) and their receptors (neuropilins 1 and 2, plexins A1, A2, A3, B2, and D1) in undifferentiated and differentiated mouse podocytes using reverse transcriptase-polymerase chain reaction (RT-PCR). All class 3 semaphorins, neuropilins 1 and 2 are expressed by undifferentiated and differentiated podocytes at similar levels. Differentiated podocytes expressed 2-4-fold higher plexin A1, A2, and A3 mRNA levels than undifferentiated podocytes. To examine semaphorin regulation, we exposed podocytes to recombinant sema 3A. Sema 3A decreased semaphorin 3B, plexin A1, A3, and D1 >/=50% and reduced plexin A2 mRNA to undetectable levels. To identify sema 3A function in podocytes, we examined whether sema 3A regulates slit diaphragm proteins and podocyte survival. Sema 3A induced a dose-response podocin downregulation and decreased its interaction with CD2-associated protein and nephrin, as determined by Western analysis and co-immunoprecipitation. To evaluate sema 3A role in podocyte survival, we quantified podocyte apoptosis using a caspase 3 activity marker. Sema 3A induced a 10-fold increase in podocyte apoptosis and significantly decreased the activity of the Akt survival pathway. Our data indicate that (1) immortalized podocytes in culture have a functional autocrine semaphorin system that is regulated by differentiation and ligand availability; (2) sema 3A signaling regulates the expression and interactions of slit-diaphragm proteins and decreases podocyte survival.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4.

The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous studies from our laboratory concerned with evaluating early changes in gene expression induced by aplidine in MOLT-4 cells have shown that the drug decreases the expression of VEGFR-1 (Marchini et al. Proc Am Assoc Cancer Res 2000; 41: 833). Here, we report the ability of aplidine to block the VEGF/VEGFR-1 loop. We found that aplidine blocked VEGF secretion that was temporally followed by a decrease in both VEGF and VEGFR-1 production. Aplidine did not directly affect either VEGF transcription or stabilization of its mRNA. Transfection of MOLT-4 cells with an antisense VEGF cDNA construct, resulted in inhibition of colony formations. One clone, transfected with sense VEGF cDNA, secreting 8-10 times more VEGF than parental cells, was less sensitive to aplidine-induced cytotoxicity and apoptosis than control cells. Moreover, addition of VEGF in the medium decreased the activity of aplidine in MOLT-4 cells. These data demonstrate that aplidine inhibits the growth and induces apoptosis in MOLT-4 cells through the inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells.

Antineoplastic Agents↗
PubMed1998

Activation of NF-kappa B by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade.

Raf-1 kinase has been implicated in the induction of NF-kappa B activity by serum growth factors, phorbol ester and PTK oncogenes. Here we show that Raf activation of NF-kappa B, as measured in reporter gene assays, occurs indirectly and requires the stress kinase cascade. The stress pathway presumably becomes activated through induction of an autocrine loop by activated Raf (Raf-BXB) as suramin, the tyrphostin AG1478 and a dominant negative mutant of the EGF-R blocked NF-kappa B activation. Raf-BXB synergizes with SAPKs and a dominant negative mutant of SEK significantly reduces activation of NF-kappa B consistent with a role of this signaling pathway in the activation of NF-kappa B.

3T3 Cells↗
PubMed2000

A conditionally-active form of MEK1 results in autocrine tranformation of human and mouse hematopoietic cells.

The Raf/MEK/MAP kinase cascade plays a critical role in transducing growth signals from activated cell surface receptors. Using deltaMEK1:ER, a conditionally-active form of MEK1, we demonstrate the ability of this dual specificity protein kinase to abrogate the cytokine-dependency of the human and murine hematopoietic cells lines TF-1, FDC-P1 and FL5.12. Cytokine-independent cells were obtained from TF-1, FDC-P1 and FL5.12 cells at frequencies of 2.5 x 10(-3), 5 x 10(-5) and 10(-7) respectively, indicating that not all cells expressing deltaMEK1:ER were factor-independent. In general, cells that were converted to a cytokine-independent phenotype displayed a higher level of MAP kinase activity in response to deltaMEK1:ER activation than those that remained cytokine-dependent. deltaME-K1:ER-responsive cells could be maintained long-term in the presence of beta-estradiol as well as the estrogen-receptor antagonist 4-Hydroxy-Tamoxifen and the anti-estrogen ICI 164383. Removal of hormone led to the rapid cessation of cell growth in a manner similar to that observed when cytokine is withdrawn from the parental cells. Treatment of deltaMEKI:ER-responsive cells with a specific and selective inhibitor, PD98059, prevented growth in response to beta-estradiol. GM-CSF mRNA transcripts were detected in the MEK1-responsive cells indicating that the activated deltaMEK1:ER may induce a pathway leading to autocrine proliferation. Treatment of MEK1-responsive cells with an anti-GM-CSF antibody, but not a control antibody, suppressed cell growth. The cell lines described here will be useful for elaborating the ability of the MAP kinase pathway to regulate cell proliferation in hematopoietic cells.

Animals↗
PubMed2002

Autocrine heregulin generates growth factor independence and blocks apoptosis in colon cancer cells.

The aim of this study was to determine whether constitutive ErbB2 activation controls growth and apoptosis in colon cancer cells. Growth arrested GEO cells showed constitutive activation of ErbB2 in the absence of exogenous growth factors or serum supplementation. Higher levels of heregulin and ErbB2 activation were observed in the growth-arrested state and cell cycle re-entry was independent of exogenous growth factors. Blockade of ErbB2 activation by heregulin neutralizing antibodies and by AG879 resulted in prevention of cell cycle re-entry. This indicated that autocrine heregulin activity was responsible for growth factor independence and for cell cycle re-entry. Activation of ErbB2 was the result of heregulin mediated interaction with ErbB3 and generated downstream activation of the ERK and the PI3K/AKT pathways. Heregulin neutralizing antibody treatment of growth arrested GEO cells also generated apoptosis as reflected by PARP cleavage and DNA fragmentation indicating a cell survival signal was also induced by the constitutively activated ErbB2. The activation of AKT but not the MAPK pathway was responsible for cell survival in these cells.

Adenocarcinoma↗
PubMed2002

Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine.

Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, but it is not clear whether HGF stimulates or inhibits hepatocarcinogenesis. We previously reported that HGF transgenic mice under the metallothionein gene promoter developed benign and malignant liver tumors spontaneously after 17 months of age. To elucidate the role of HGF in hepatocarcinogenesis, diethylnitrosamine (DEN) was administered to HGF transgenic mice. HGF overexpression accelerated DEN-induced hepatocarcinogenesis, often accompanied by abnormal blood vessel formation. In this study, 59% of transgenic males (versus 20% of wild-type males) and 39% of transgenic females (versus 2% of wild-type females) developed either benign or malignant liver tumors by 48 weeks (P<0.005, P<0.001, respectively). Moreover, 33% of males and 23% of female transgenic mice developed hepatocellular carcinoma (HCC), while none of the wild-type mice developed HCC (P<0.001, P<0.005, respectively). Enhanced kinase activity of the HGF receptor, Met, was detected in most of these tumors. Expression of vascular endothelial growth factor (VEGF) was up-regulated in parallel with HGF transgene expression. Taken together, our results suggest that HGF promotes hepatocarcinogenesis through the autocrine activation of the HGF-Met signaling pathway in association with stimulation of angiogenesis by HGF itself and/or indirectly through VEGF.

Alkylating Agents↗
PubMed2005

Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells.

Constitutive expression of cyclin D1 is a frequent abnormality in human cancer and sustains the transformed phenotype. We have previously demonstrated that cyclin D1 is constitutively expressed in human BON neuroendocrine tumour cells due to an autocrine insulin-like growth factor-I (IGF-I) loop. Here we examine the regulation of cyclin D1 expression by endogenously released IGF-I in BON cells. Cyclin D1 expression in these cells was found to be dependent on phosphatidylinositol 3-kinase (PI3-K), but independent of the extracellular signal-regulated kinase cascade. Ras- and Rac-GTPases were found to be upstream activators of cyclin D1 expression, whereas protein kinase B/AKT and nuclear factor kappa B (NFkappaB) could be established as downstream mediators of cyclin D1 transcription in response to endogenously released IGF-I in these cells. In addition, the Ras/PI3-K/AKT/Rac/NFkappaB/cyclin D1 signaling cascade triggered by endogenously released IGF-I is sufficient to sustain Rb phosphorylation and cdk4 kinase activity in BON cells. In conclusion, our data provide the first comprehensive map of the signaling events elicited by endogenously released IGF-I leading to constitutive cyclin D1 expression in human neuroendocrine tumour cells.

Autocrine Communication↗
PubMed2004

Terminal differentiation of Sol 8 myoblasts is retarded by a transforming growth factor-beta autocrine regulatory loop.

In DM (differentiation medium), Sol 8 myoblasts spontaneously form myotubes and express the betaMHC (beta-myosin heavy chain), their main marker of terminal differentiation. This marker is detectable at 24 h, and increases up to 72 h. Our aim was to define temporal effects of TGFbeta (transforming growth factor beta) on betaMHC expression in Sol 8 cells. TGFbeta1 (1 ng/ml) added at time zero to DM decreased MyoD expression and completely inhibited betaMHC expression in Sol 8 cells. This inhibition of betaMHC expression was progressively lost when TGFbeta1 was added from 8 to 34 h. After 34 h, the cells were irreversibly differentiated, and TGFbeta1 did not inhibit betaMHC accumulation any longer. Two independent approaches showed that a TGFbeta autocrine regulatory loop retarded and partially impaired Sol 8 cell terminal differentiation. First, permanent immunoneutralization of the active TGFbetas released by the cells into DM increased betaMHC levels at 72 h compared with controls. Secondly, a dominant-negative mutant of the TGFbeta type II receptor was overexpressed in Sol 8 cells under the control of the betaMHC promoter. Both the dominant-negative receptor and the betaMHC gene were expressed after 24 h in DM. The delayed blocking of the TGFbeta signalling pathway by the dominant-negative receptor was as effective as permanent immunoneutralization to promote betaMHC expression. To conclude, TGFbeta inhibits Sol 8 cell terminal differentiation within a narrow time interval (24-34 h) that coincides with the onset of betaMHC expression.

Animals↗