Mechanism of activation of the TGF-β receptor

Wrana, Jeffrey L.; Attisano, Liliana; Wieser, Rotraud; Ventura, Francesc; Massagué, Joan

doi:10.1038/370341a0

Cited by 2,164 publications

(1,622 citation statements)

References 42 publications

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“…37 TGF-b is a physiological regulator of prostatic growth 38,39 via its ability to inhibit prostate epithelial cell proliferation and activate apoptosis in the presence of physiological levels of androgens. 38,40 Interestingly, TGF-b is overexpressed in the malignant prostate when compared with the normal gland.…”

Section: Discussionmentioning

confidence: 99%

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

Anglin

Glassman

Kyprianou

2002

Prostate Cancer Prostatic Dis

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a 1 -Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based a 1 -antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an a 1 -adrenoceptor independent mechanism potentially involving activation of the TGF-b signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived a 1 -adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases.

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Section: Discussionmentioning

confidence: 99%

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

Anglin

Glassman

Kyprianou

2002

Prostate Cancer Prostatic Dis

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“…Transforming growth factor-b family members transduce their signals across the plasma membrane by inducing the formation of heteromeric complexes of specific type I and type II serine/threonine kinase receptors (Heldin et al, 1997). The type I receptor (also termed activin receptor-like kinase (ALK)) is phosphorylated and activated by the type II receptor (Wrana et al, 1994), and initiates intracellular signaling through activation of downstream signaling components, including the phosphorylation of receptor-regulated (R-) Smads at their extreme carboxyl-terminal serine residues. Phosphorylated R-Smads can recruit a common-partner Smad4 to form heteromeric complexes that translocate to the nucleus, where they regulate the transcription of TGF-b target genes (Shi and Massague´, 2003).…”

Section: Introductionmentioning

confidence: 99%

ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

et al. 2006

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Transforming growth factor-b (TGF-b) elicits a potent growth inhibitory effect on many normal cells by binding to specific serine/threonine kinase receptors and activating specific Smad proteins, which regulate the expression of cell cycle genes, including the p21 cyclin-dependent kinase (CDK) inhibitor gene. Interestingly, cancer cells are often insensitive to the anti-mitogenic effects of TGF-b for which the molecular mechanisms are not well understood. In this study, we found that the candidate prostate cancer susceptibility gene ELAC2 potentiates TGF-b/Smadinduced transcriptional responses. ELAC2 associates with activated Smad2; the C-terminal MH2 domain of Smad2 interacts with the N-terminal region of ELAC2. Small interfering siRNA-mediated knock-down of ELAC2 in prostate cells suppressed TGF-b-induced growth arrest. Moreover, ELAC2 was shown to specifically associate with the nuclear Smad2 partner, FAST-1 and to potentiate the interaction of activated Smad2 with transcription factor Sp1. Furthermore, activation of the p21 CDK inhibitor promoter by TGF-b is potentiated by ELAC2. Taken together our data indicate an important transcriptional scaffold function for ELAC2 in TGF-b/ Smad signaling mediated growth arrest.

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“…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%

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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Mechanism of activation of the TGF-β receptor

Cited by 2,164 publications

References 42 publications

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

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

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