Transforming Growth Factor-β (TGF-β) Type I Receptor/ALK5-dependent Activation of the GADD45β Gene Mediates the Induction of Biglycan Expression by TGF-β

Ungefroren, Hendrik; Groth, S.; Ruhnke, Maren; Kalthoff, Holger; Fändrich, F.

doi:10.1074/jbc.m411925200

Cited by 44 publications

(55 citation statements)

References 34 publications

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“…Interestingly, RImL45-TD inhibited phosphorylation of Smad2 and repression of the Myc promoter in response to exogenous ligand and in some assays relieved the autoinhibitory effect of endogenously produced TGF-b (see above), together suggesting that this mutant acts in a dominant-negative fashion for Smad-mediated responses triggered by either exogenous or endogenous TGF-b. Such an effect has been observed in TGF-b regulation of the matrix proteoglycan biglycan in PANC-1 cells (Ungefroren et al, 2005). A recent study by Tian et al (2004) investigating the in vitro and the in vivo function of RImL45 in Ha-ras-transformed breast cancer cells found that this mutant, as in our model, selectively interfered with activation of endogenous Smad2 and Smad3 and enhanced the malignancy of xenografted tumors of the well-differentiated MIII cell line derived from MCF10A cells.…”

Section: Tgf-b Receptor Type I In Tgf-b-induced Tumor Suppressionsupporting

confidence: 68%

“…For analysis of the antiproliferative response, we employed PANC-1 cells stably expressing ALK5-KR from a retroviral vector. These cells, too, have been characterized in a previous publication and shown to be insensitive to TGF-b-induced Smad activation and biglycan induction (Ungefroren et al, 2005). Notably, TGF-b-induced growth inhibition, as measured by DNA synthesis, was relieved in these cells compared with vector-transduced and parental controls ( Figure 1c) and this was associated with a failure to upregulate expression of p21 WAF1 (data not shown).…”

Section: Resultsmentioning

confidence: 59%

“…To establish whether the antiproliferative response to this growth factor is TbRII-dependent, we employed PANC-1 cells retrovirally transduced in a stable fashion with dominant-negative TbRII (D404G). These cells have been demonstrated previously to be refractory to TGF-b-induced stimulation of reporter gene (3TP-lux) activity and matrix gene expression (Ungefroren et al, 2005). Importantly, TbRII-DG-transduced PANC-1 cells were unable to respond to this growth factor with growth inhibition as were MiaPaCa2 cells, known to harbor a loss-of-function mutation in TbRII (Freeman et al, 1995) (Figure 1a).…”

Section: Resultsmentioning

confidence: 67%

“…In a previous publication, we have demonstrated that ectopic expression of ALK5-TD, but not RImL45-TD, can mimic the TGF-b-induced activation of the p6SBE-Luc reporter in PANC-1 cells (Ungefroren et al, 2005). To assess if ALK5-TD on its own can also transcriptionally repress the Myc gene (which is a prerequisite for induction of p21 WAF1 (Claassen and Hann, 2000) and is accomplished by TGF-b through binding of Smad3 to a repressive Smadbinding element in the Myc promoter (Frederick et al, 2004), we performed transient co-transfection experiments with pMYC-TA-Luc along with ALK5-TD or RImL45-TD.…”

Section: Resultsmentioning

confidence: 88%

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Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Schniewind¹,

Groth²,

Müerköster³

et al. 2007

Oncogene

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In the present study, we have analysed the effects of transforming growth factor-beta (TGF-b) signaling on the growth behavior of pancreatic carcinoma cells in vitro and on their tumorigenicity in vivo. Ectopic expression of dominant-negative mutants of the TGF-b type II receptor or type I receptor/activin receptor-like kinase 5 (ALK5) in TGF-b-sensitive pancreatic ductal adenocarcinoma PANC-1 cells prevented the TGF-b-induced activation of transfected Smad-responsive reporter genes and growth arrest. The growth-inhibitory effect was mimicked by stable expression of kinase-active ALK5 (ALK5-T204D), and was dependent on ALK5's ability to activate Smad signaling, as a ALK5-derived mutant with an intact kinase domain but deficient in its ability to activate Smads (RImL45) failed to suppress proliferation in the absence of added TGF-b. Moreover, this mutant often displayed opposite effects to those of ALK5-TD and blocked various ligand-induced responses in vitro, indicating that it acts in a dominant-negative fashion to inhibit endogenous wild-type receptors. ALK5-TD-, but not RImL45-TDtransduced cells underwent epithelial-to-mesenchymal transition, exhibited a higher ratio of thrombospondin-1 to vascular endothelial growth factor-A expression and upregulated various metastasis-associated genes. Upon orthotopic transplantation of PANC-1 clones into immunodeficient mice, ALK5-TD, but not RImL45-TD, greatly reduced tumor size and induced the formation of liver metastases in otherwise non-metastatic PANC-1 cells. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-b in pancreatic tumor cells.

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Section: Tgf-b Receptor Type I In Tgf-b-induced Tumor Suppressionsupporting

confidence: 68%

Section: Resultsmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 88%

See 2 more Smart Citations

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Schniewind¹,

Groth²,

Müerköster³

et al. 2007

Oncogene

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“…We found 1.8-fold upregulation of this proteins in pancreatic tumor treated with Hsp90 inhibitor. In addition, it is worth noting that biglycan is associated with the transforming growth factor-h pathway in pancreatic cancer (33).…”

Section: Itraq-labeled Ms and Gene Expression Microarray Analysismentioning

confidence: 99%

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Song

Chaerkady

Tan

et al. 2008

Molecular Cancer Therapeutics

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Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose-and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

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Antitumor activity of ALK1 in pancreatic carcinoma cells

Ungefroren¹,

Schniewind²,

Groth³

et al. 2007

Intl Journal of Cancer

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In this study, the authors investigated the expression of activin receptor-like kinase 1 (ALK1) in pancreatic carcinoma and evaluated its potential role as a tumor suppressor in vitro and in vivo. Endogenous ALK1 expression was demonstrated by immunohistochemistry in both pancreatic tumor tissue and peritumoral normal tissue from 6 patients and by RT-PCR in 8/12 established pancreatic cancer cell lines. Ectopic expression of a constitutively active (ca) ALK1 mutant in TGF-b sensitive PANC-1 and COLO-357 cells augmented transcriptional activation of a Smad2/3 responsive reporter, and slowed down basal growth in vitro. Both effects were further enhanced by TGF-b/ALK5 stimulation, suggesting largely independent nuclear Smad signaling by both type I receptors. Upon orthotopic transplantation of PANC-1-caALK1 into immunodeficient mice, tumor size was strongly reduced and was associated with a lower microvessel density in the PANC-1-caALK1-derived tumors. In vitro, this mutant efficiently blocked TGF-b-induced epithelial-to-mesenchymal transdifferentiation and suppressed TGF-b/ALK5-mediated activation of the p38 MAPK pathway. Mechanistically, caALK1 silenced MyD118, an immediate TGF-b target gene whose protein product, GADD45b, couples Smad signaling to p38 activation. These results show that ALK1 activation in pancreatic tumor cells is antioncogenic by inducing ALK5-independent growth inhibition and by blocking TGF-b/ALK5-mediated epithelial-to-mesenchymal transdifferentiation and, possibly, invasion and metastatic progression. ' 2007 Wiley-Liss, Inc.

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Transforming Growth Factor-β (TGF-β) Type I Receptor/ALK5-dependent Activation of the GADD45β Gene Mediates the Induction of Biglycan Expression by TGF-β

Cited by 44 publications

References 34 publications

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Antitumor activity of ALK1 in pancreatic carcinoma cells

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