TGFβ signals through a heteromeric protein kinase receptor complex

Wrana, Jeffrey L.; Attisano, Liliana; Cárcamo, Juan M.; Zentella, Alejandro; Doody, Jacqueline; Laiho, Marikki; Wang, Xiao Fan; Massagué, Joan

doi:10.1016/0092-8674(92)90395-s

Cited by 1,439 publications

(1,223 citation statements)

References 49 publications

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“…SRF itself increased the basal activity of 3TP-lux. This effect may be mediated through the three consecutive activator protein-1 (AP-1)-binding elements present in the 3TP-Lux reporter (Wrana et al, 1992) because c-fos, a component of the AP-1 complex, is transcriptionally activated by SRF (Treisman, 1992;Paradis et al, 1996.). As a positive control of the SRF effect, we examined the effect of SRF on the serum response element (SRE-Luc) reporter activity ( Figure 2e).…”

Section: Serum Represses Tgf-b1/smad3-dependent Transcriptionmentioning

confidence: 99%

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

et al. 2006

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Serum response factor (SRF) is a widely expressed transcription factor involved in immediate-early and tissue-specific gene expression, cell proliferation and differentiation. We defined a new role of SRF as a nuclear repressor of the tumor growth factor b1 (TGF-b1) growth-inhibitory signal during cell proliferation. We show that SRF significantly inhibits the TGF-b1/Smaddependent transcription by associating with Smad3. SRF causes resistance to the TGF-b1 cytostatic response by directly repressing the Smad transcriptional activity and Smad binding to DNA. Furthermore, we demonstrated that overexpression of SRF markedly decreases the level of Smad3 complex binding to the promoters of Smad3 target genes, p15 INK4b and p21 Cip1 . This leads to the inhibition of expression of TGF-b1-responsive genes. SRF therefore acts as a nuclear repressor of Smad3-mediated TGF-b1 signaling.

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Section: Serum Represses Tgf-b1/smad3-dependent Transcriptionmentioning

confidence: 99%

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

et al. 2006

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“…The TGF-b-responsive promoter-luciferase construct was stably expressed in the GEO cells. Following 5 aza C treatment, cells were subjected to treatment with 5 ng/ml TGF-b1 on day 7 for 24 h, and luciferase activity was then determined (Wrana et al, 1992). TGF-b had no e ect on the control GEO cells, but 5 aza C-treated cells showed two and sixfold induction in the absence and presence of TGF-b1, respectively (Figure 4).…”

Section: Responsiveness To Tgf-b1mentioning

confidence: 99%

“…The TGF-b responsive plasminogen activator inhibitor promoter-luciferase reporter construct (p3TP-Lux) and TGF-b RI promoter-luciferase reporter construct (RI-Luc) were used to determine TGF-b sensitivity and RI promoter activities, respectively (Bloom et al, 1996;Wrana et al, 1992). The p3TP-Lux vector (15 mg) or TGF-b RI-Luc (15 mg) along with a hygromycin containing plasmid (2 mg) were stably transfected into GEO cells using a Bio-Rad electroporator at 250 mv and 960 microfarads.…”

Section: Luciferase Assaymentioning

confidence: 99%

“…While RI and RII are glycoproteins of 53 and 75 kDa, respectively, RIII is a 280 ± 330 kDa proteoglycan (Yingling et al, 1995). RI and RII are serine/ threonine kinases which form an active heterooligomeric complex and are the key players in the TGF-b mediated signaling cascade (Franzen et al, 1993;Lin et al, 1992;Wrana et al, 1992Wrana et al, , 1994. Recent studies indicate that, following TGF-b binding and subsequent activation of RI by RII, RI phosphorylates Smad2 and/or Smad3, which can then associate with Smad4 and translocate to the nucleus where binding to the target DNA or other DNA binding proteins occurs.…”

Section: Introductionmentioning

confidence: 99%

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Repression of transforming growth factor-β receptor type I promoter expression by Sp1 deficiency

Periyasamy

Ammanamanchi²,

Tillekeratne

et al. 2000

Oncogene

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In this report, we describe the mechanism of TGF-b receptor type I (RI) repression in the GEO human colon carcinoma cells. Treatment of GEO cells with the DNA methyltransferase inhibitor, 5 azacytidine induced RI expression and restored TGF-b response. A stably transfected RI promoter-reporter construct (RI-Luc) expressed higher activity in the 5 aza C treated GEO cells, suggesting the activation of a transactivator for RI transcription. Gel shift analysis indicated enhanced binding of proteins from the 5 aza C treated nuclear extracts to radiolabeled Sp1 oligonucleotides speci®cally contained in the RI promoter. Protein stability studies after cyclohexamide treatment suggested an increase in the Sp1 protein stability from the 5 aza C treated GEO cells. Further, transfection of Sp1 cDNA into untreated GEO control cells increased RI promoter activity and thus induced RI expression. 5 aza C mediated Sp1 expression in Sp1 de®cient GEO colon and MCF-7 breast cancer cells also enhanced the activity of several other Sp1 dependent promoters such as TGFb receptor type II (RII), Cyclin A and p21/waf1/cip1. These results indicate that restoration of Sp1 in several di erent types of Sp1 de®cient cells leads to enhanced activation of a wide range of Sp1 dependent promoters. Oncogene (2000) 19, 4660 ± 4667.

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“…Loss of TGF-b expression and resistance to the growth inhibition through TGF-b seems to be a late event in tumor progression (Haddow et al, 1991). Mutations of the type II receptor can interrupt the signal transduction pathway by dominant negative mechanisms (Wrana et al, 1992;Brand et al, 1993;Carcamo et al, 1995). Inactivation or reduced expression of the type II receptor has been shown to occur for example in colon cancer cells with microsatellite instability, in a cutaneous T-cell lymphoma, in various human breast tumor cell lines and in a retinoblastoma cell line (Kimchi et al, 1988;Kalkhoven et al, 1995;Markowitz et al, 1995;Knaus et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

et al. 1998

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The role of Transforming growth factor beta (TGF-b) in carcinogenesis is complex. There are reports on both tumor inhibition and tumor promotion by TGF-b. To elucidate the complex role of TGF-b in epithelial carcinogenesis, we generated transgenic mice overexpressing a dominant negative type II TGF-b receptor in the basal cell compartment and in follicular cells of the skin. Despite the reduced responsiveness of transgenic keratinocytes to TGF-b, both proliferation and di erentiation were normal in non-irritated epidermis of these transgenic mice. Thus, interruption of signaling of all three isoforms of TGF-b in basal and follicular cells does not disturb tissue homeostasis. However, during tumor promotion transgenic mice showed an elevated level of proliferation in the epidermis. This hyperproliferation correlated with a very early onset of carcinoma development and a malignant conversion frequency of 30% from benign papillomas to carcinomas. By comparison, the conversion frequency in wild-type mice of this strain has previously been reported as 5.5%. Even without induction of hyperproliferation by tumor promoters, transgenic mice developed far more carcinomas as controls when treated with a carcinogen. This result indicates that there is a synergistic e ect between loss of TGF-b responsiveness and mutations caused by initiation with a carcinogen leading to an endogeneous tumor promotion in initiated cells only.

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TGFβ signals through a heteromeric protein kinase receptor complex

Cited by 1,439 publications

References 49 publications

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

Repression of transforming growth factor-β receptor type I promoter expression by Sp1 deficiency

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

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