A zinc‐finger transcription factor induced by TGF‐β promotes apoptotic cell death in epithelial Mv1Lu cells

Chalaux, Elisabet; López-Rovira, Teresa; Rosa, José Luís; Pons, Gabriel; Boxer, Linda M.; Bartrons, Ramón; Ventura, Francesc

doi:10.1016/s0014-5793(99)01051-0

Cited by 97 publications

(73 citation statements)

References 36 publications

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“…The role of this nuclear factor has not yet been characterised in prostate growth, but it might potentially involve the activation of proapoptotic mechanisms, such as the downregulation of bcl-2 as reported in lung epithelial cells (Chalaux et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

2003

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Previous studies documented the ability of quinazoline-based a1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an a1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-b1 (TGF-b1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-b1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgenindependent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based a1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21 WAF-1 and IkBa (inhibitor of NF-kB alpha). Relative quantitative reverse transcription -polymerase chain reaction analysis revealed induction of several TGF-b1 signalling effectors: Induction of mRNA for Smad4 and the TGF-b1-regulated apoptosis-inducing transcription factor TGF-b1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of IkBa at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-b mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-b1 signalling effectors and subsequently IkBa. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.

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Section: Discussionmentioning

confidence: 99%

“…The TGF-b1-inducible early gene (TIEG1) is another factor that induces apoptosis in breast, lung and kidney cells (Tachibana et al, 1997;Chalaux et al, 1999;Hefferan et al, 2000), potentially by downregulating the antiapoptotic protein bcl-2 (Chalaux et al, 1999).…”

mentioning

confidence: 99%

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

2003

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“…3) (Motyl et al, 1998;Francis et al, 2000;Chipuk et al, 2001;Kim et al, 2001). In addition, TGF-b-mediated induction of Id3 expression in primary B lymphocyte progenitors (Kee et al, 2001), TIEG in mink lung epithelial and Hep3B cells (Chalaux et al, 1999;Ribeiro et al, 1999), and TGFb-stimulated clone 22 (TSC-22) in gastric carcinoma cells (Ohta et al, 1997), have been implicated in apoptosis. However, whether Smads are directly regulating the expression of these genes with role in apoptosis is not known.…”

Section: Regulation Of Apoptosis By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

400

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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“…The threshold for analysis was determined empirically and set at 235 (grey scale 0-1,000). For the femoral midshaft, 10 slices (120 μm) of bone were evaluated and total cross-sectional tissue volume (cortical and marrow volume, mm 3 ), cortical volume (mm 3 ), marrow volume (mm 3 ), and cortical thickness (μm) were measured. For the femoral metaphysis, 125 slices (1.5 mm) of bone were evaluated and included secondary spongiosa only.…”

Section: Micro-ctmentioning

confidence: 99%

“…TIEG is expressed in numerous tissues [2][3][4][5][6][7] and is a member of the Krüppel-like family of transcription factors (KLF-10) which are known to be involved in antiproliferative and apoptotic inducing functions similar to those initiated by TGFβ action [8][9][10]. These factors bind to Sp-1-GC rich DNA elements via their zinc fingers and regulate the expression of genes involved in cell growth, differentiation and apoptosis [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

TIEG-null mice display an osteopenic gender-specific phenotype

Hawse

Iwaniec

Bensamoun

et al. 2008

Bone

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TGFβ Inducible Early Gene-1 (TIEG) was originally cloned from human osteoblasts (OB) and has been shown to play an important role in TGFβ/Smad signaling, regulation of gene expression and OB growth and differentiation. To better understand the biological role of TIEG in the skeleton, we have generated congenic TIEG-null (TIEG -/-) mice in a pure C57BL/6 background. Through the use of DXA and pQCT analysis, we have demonstrated that the femurs and tibias of two-month-old female TIEG -/-mice display significant decreases in total bone mineral content, density, and area relative to wild-type (WT) littermates. However, no differences were observed for any of these bone parameters in male mice. Further characterization of the bone phenotype of female TIEG -/-mice involved mechanical 3-point bending tests, micro-CT, and histomorphometric analyses of bone. The 3-point bending tests revealed that the femurs of female TIEG -/-mice have reduced strength with increased flexibility compared to WT littermates. Micro-CT analysis of femurs of two-month-old female TIEG -/-mice revealed significant decreases in cortical bone parameters compared to WT littermates. Histomorphometric evaluation of the distal femur revealed that female TIEG -/-mice also display a 31% decrease in cancellous bone area, which is primarily due to a decrease in trabecular number. At the cellular level, female TIEG -/-mice exhibit a 42% reduction in bone formation rate which is almost entirely due to a reduction in double labeled perimeter. Differences in mineral apposition rate were not detected between WT and TIEG -/-mice. Taken together, these findings suggest that female TIEG -/-mice are osteopenic mainly due to a decrease in the total number of functional/mature OBs.

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A zinc‐finger transcription factor induced by TGF‐β promotes apoptotic cell death in epithelial Mv1Lu cells

Cited by 97 publications

References 36 publications

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

Regulation of cell proliferation by Smad proteins

TIEG-null mice display an osteopenic gender-specific phenotype

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