Rb/E2F4 and Smad2/3 link survivin to TGF-β-induced apoptosis and tumor progression

Yang, Jiayi; Song, Kyung; Krebs, Tracy L.; Jackson, Mark W.; Danielpour, David

doi:10.1038/onc.2008.165

Cited by 66 publications

(70 citation statements)

References 40 publications

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“…In particular, it will be important to determine whether a defect in transforming growth factor-b (TGFb) signaling, which was identified in immortal MRC5hTERT and WI38hTERT cells, contributes to the high level of survivin expressed in these cells (Milyavsky et al, 2007). This possibility is supported by two recent studies that have shown TGFb suppresses expression of survivin (Wang et al, 2008;Yang et al, 2008).…”

Section: Discussionmentioning

confidence: 74%

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

et al. 2009

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These investigations demonstrate that expression of the inhibitor of apoptosis family member, survivin, is dramatically increased during immortalization of nontransformed human fibroblasts that were transduced with telomerase reverse transcriptase (hTERT). Expression of survivin in immortalized fibroblasts peaked during G 2 /M phase of the cell cycle. However, the upregulation of survivin was dissociated from the rate of proliferation and proportion of G 2 /M cells. Depletion of survivin from immortal fibroblasts increased sensitivity to stress-induced apoptosis and resulted in an accumulation of cells with 4N DNA content. Conversely, overexpression of survivin in mortal fibroblasts conferred resistance to apoptosis. In contrast, very low levels of survivin in proliferating parental fibroblasts had no bearing on sensitivity to apoptosis. The upregulation of survivin did not appear to be a direct consequence of hTERT transduction. However, repression of hTERT resulted in the rapid downregulation of survivin in telomerase-immortalized fibroblasts and tumor cell lines, but not in cells immortalized via an Alternative Lengthening of Telomeres mechanism. These results have important therapeutic implications, as telomerase and survivin are both broadly expressed in human cancers. Selection during the immortalization process for cells expressing high levels of survivin may account for the abundance of survivin in diverse tumor types.

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Section: Discussionmentioning

confidence: 74%

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

et al. 2009

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“…Belinostat treatment did induce p21 WAF1/CIP1 , and induction of this CDKI was required for SAHA-mediated degradation of survivin in colon cancer cells (55). However, Danielpour and co-workers (56) reported that TGF␤-mediated repression of survivin transcription requires Smad interaction with the promoter.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β (TGFβ) Receptor II Leading to Cancer Cell Death

Chowdhury

Howell

Teggart

et al. 2011

Journal of Biological Chemistry

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Survivin is a cancer-associated gene that functions to promote cell survival, cell division, and angiogenesis and is a marker of poor prognosis. Histone deacetylase inhibitors induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes in cancer cells. In association with increased expression of the tumor suppressor gene transforming growth factor ␤ receptor II (TGF␤RII) induced by the histone deacetylase inhibitor belinostat, we observed repressed survivin expression. We investigated the molecular mechanisms involved in survivin down-regulation by belinostat downstream of reactivation of TGF␤ signaling. We identified two mechanisms. At early time points, survivin protein half-life was decreased with its proteasomal degradation. We observed that belinostat activated protein kinase A at early time points in a TGF␤ signaling-dependent mechanism. After longer times (48 h), survivin mRNA was also decreased by belinostat. We made the novel observation that belinostat mediated cell death through the TGF␤/protein kinase A signaling pathway. Induction of TGF␤RII with concomitant survivin repression may represent a significant mechanism in the anticancer effects of this drug. Therefore, patient populations exhibiting high survivin expression with epigenetically silenced TGF␤RII might potentially benefit from the use of this histone deacetylase inhibitor.The mutational events involved in the initiation and progression of colorectal cancer have been well documented (1). However, it is now recognized that in addition to these alterations in DNA sequence epigenetic modifications of the genome play a major role in contributing to the malignant phenotype (1, 2). The critical balance between histone acetylation by histone acetyltransferases and deacetylation by histone deacetylases (HDACs) 3 represents a key epigenetic layer involved in gene regulation (3). The class I HDACs are overexpressed in many tumor types compared with normal tissues (4), and this overexpression is generally associated with poor prognosis (5, 6). These findings have resulted in the development of drugs that target HDACs. The second generation HDAC inhibitors (HDACis) target class I and II HDACs. These drugs induce differentiation, cell growth arrest, and apoptosis in cell lines in vitro and in vivo indicating that the increased activity of these enzymes in cancer contributes to tumor progression (7-9). However, the key mechanisms and pathways through which HDAC inhibition leads to tumor cell apoptosis have not been well defined.Transforming growth factor ␤ (TGF␤) signaling has been shown to contribute to a variety of cellular functions including growth inhibition and induction of differentiation and apoptosis as well as cell motility and adhesion (10). It has been demonstrated that transcriptional loss of TGF␤ receptor expression leading to attenuation of TGF␤ signaling is a frequent occurrence in a wide range of cancers in vitro and in vivo and is associated with poor patient prognosis (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(...

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“…Smad2/3 signaling may augment apoptosis by altering cell cycle repressor elements or reducing the antiapoptotic protein Bcl-2. 37,38 Smad pathways have been implicated in TGF-b-mediated apoptosis of other epithelial cells, 39 but one study concluded that TGF-b1 augmented proximal tubule apoptosis independent of Smad signaling. 13 This study used Smad7 overexpression to inhibit Smad2, which might not be ideal because Smad7 per se promotes apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury

Gewin

Vadivelu²,

Neelisetty³

et al. 2012

Journal of the American Society of Nephrology

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TGF-b is a profibrotic growth factor in CKD, but its role in modulating the kidney's response to AKI is not well understood. The proximal tubule epithelial cell, which is the main cellular target of AKI, expresses high levels of both TGF-b and its receptors. To determine how TGF-b signaling in this tubular segment affects the response to AKI, we selectively deleted the TGF-b type II receptor in the proximal tubules of mice. This deletion attenuated renal impairment and reduced tubular apoptosis in mercuric chloride-induced injury. In vitro, deficiency of the TGF-b type II receptor protected proximal tubule epithelial cells from hydrogen peroxide-induced apoptosis, which was mediated in part by Smad-dependent signaling. Taken together, these results suggest that TGF-b signaling in the proximal tubule has a detrimental effect on the response to AKI as a result of its proapoptotic effects.

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Rb/E2F4 and Smad2/3 link survivin to TGF-β-induced apoptosis and tumor progression

Cited by 66 publications

References 40 publications

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β (TGFβ) Receptor II Leading to Cancer Cell Death

Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury

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