Smad7 mediates apoptosis induced by transforming growth factor β in prostatic carcinoma cells

Landström, Maréne; Heldin, Nils‐Erik; Bu, Shizhong; Hermansson, Annika; Itoh, Susumu; Dijke, Peter ten; Heldin, Carl‐Henrik

doi:10.1016/s0960-9822(00)00470-x

Cited by 123 publications

(94 citation statements)

References 9 publications

(15 reference statements)

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“…For example, in primary cultures of fetal hepatocytes, the TGFb 1 concentration required to induce apoptosis is 2.5 ng/ml, which is five times that needed to inhibit cell growth (Sanchez et al, 1996). In other systems such as murine myeloid cells, murine and human hepatocytes, rat prostate epithelial cells, and human prostate carcinoma cells, TGFb 1 concentrations at 5 to 10 ng/ml were required to induce apoptosis via different mechanisms (Chipuk et al, 2001;Landstrom et al, 2000;Perlman et al, 2001;Yamamura et al, 2000). However, treatment of the MDA-MB-231 cell with TGFb 1 at 5 ng/ml for 3 days did not induce apoptosis in our hands (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Lei

Bandyopadhyay

et al. 2002

Oncogene

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Using a cell model system established by ectopic expression of a soluble TGFb type III receptor (sRIII) containing the whole extracellular domain of the type III receptor in human breast cancer MDA-MB-231 cells, we observed that the expression of sRIII antagonized TGFb activity and inhibited both anchorage-dependent and anchorage-independent cell growth. Further studies revealed that sRIII expression induced apoptosis both in vitro and in vivo. Treatment with TGFb neutralizing antibodies or a recombinant human sRIII also induced apoptosis in the MDA-MB-231 parental cells, suggesting that the increased apoptosis after sRIII expression was specifically due to antagonization of autocrine TGFb signaling. Western blotting showed that sRIII clones had a higher PTEN expression level than the control cells did. Treatment with TGFb 1 decreased PTEN and inhibited apoptosis in sRIII cells to a level similar to that in the control cells. sRIII clones also showed a lower level of phosphorylated-Akt than the control cells, consistent with the inhibitory activity of PTEN on Akt activation. Treatment with LY294002, a specific inhibitor of Akt activator, phosphatidylinositol 3-kinase, also induced apoptosis in a dose dependent manner in the control cells. Our results suggest that autocrine TGFb signaling is necessary for the growth and survival of MDA-MB-231 cells.

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Section: Discussionmentioning

confidence: 99%

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Lei

Bandyopadhyay

et al. 2002

Oncogene

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“…Aside from its inhibitory activities against TGF-b signaling (Nakao et al, 1997), Smad7 has also been shown to exert broader functions in the cell, such as inducing apoptotic cell death Landstrom et al, 2000), and activating Jun N-terminal kinase , the latter contributing to the former effect.…”

Section: Introductionmentioning

confidence: 99%

Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling

et al. 2002

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Members of the TGF-b family of growth factors signal from the cell surface through serine/threonine kinase receptors. Intracellular propagation of the signal occurs by phosphorylation of intracellular proteins of the Smad family. Smad7 belongs to the subclass of inhibitory Smads that function as antagonists of TGF-b signaling. A yeast two-hybrid screen of a human placental cDNA expression library using full-length mouse Smad7 as bait identified Yes-Associated Protein (YAP65) as a novel Smad7-interacting protein. The association of Smad7 with YAP65 was confirmed using co-expressed tagged proteins in COS-7 cells. Deletion of the PY motif of Smad7 reduced but did not abolish YAP65-Smad7 association, suggesting the existence of several interacting domains. We demonstrate that YAP65 potentiates the inhibitory activity of Smad7 against TGF-b-induced, Smad3/4-dependent, gene transactivation. Furthermore, YAP65 augments the association of Smad7 to activated TGF-b receptor type I (TbRI), whereas YAP65(1 -301), which exerts a dominant-negative effect against Smad7-driven inhibition of TGF-b signaling, reduces these interactions. Together, these data provide the first evidence that YAP65 is a Smad7 partner that facilitates the recruitment of the latter to activated TbRI, and enhances the inhibitory activity of Smad7 against TGF-b signaling.

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“…Brodin et al (1999) have shown that after castration of rats (a TGFbinducing maneuver), there is increased phosphorylation of Smad2, increased expression of Smads 3 and 4, and increased expression of Smads 6 and 7. Induction of Smad7 is responsible for TGFb-mediated apoptosis in human prostatic carcinoma cells, as loss of Smad7 function via antisense blocks the apoptotic response to TGFb in these cells (Landstrom et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion

et al. 2003

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Transforming growth factor beta (TGFb) regulates cell adhesion, proliferation, and differentiation in a variety of cells. Smad proteins are receptor-activated transcription factors that translocate to the nucleus in response to TGFb. We demonstrate here that TGFb increases cell adhesion in metastatic PC3-M prostate cancer cells. TGFb treatment of PC3-M cells leads to nuclear translocation of R-Smad proteins. We show that Smad proteins are necessary, but not sufficient, for TGFbmediated cell adhesion. After showing that TGFb upregulated p38 MAP kinase activity in PC3-M cells, we show that inhibition of p38 MAP kinase partially blocked TGFb-mediated increase in cell adhesion, as well as nuclear translocation of Smad3. Finally, we show that Smad3 is phosphorylated by p38 MAP kinase in vitro. These findings implicate crosstalk between the MAP kinase and Smad signaling pathways in TGFb's regulation of cell adhesion in human prostate cells. This represents a mechanism by which the pleiotropic effects of TGFb may be channeled to modulate cell adhesion.

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Smad7 mediates apoptosis induced by transforming growth factor β in prostatic carcinoma cells

Cited by 123 publications

References 9 publications

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling

p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion

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