Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling

Sinibaldi, Dominic; Wharton, Walker; Turkson, James; Bowman, Tammy; Pledger, W. J.; Jove, Richard

doi:10.1038/sj.onc.1203947

Cited by 264 publications

(193 citation statements)

References 68 publications

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“…In MM, different molecular alterations lead to cyclin D overexpression or cyclin D-CDK hyperactivity (Kettunen et al, 2001;Lee et al, 2007) and a correlation between high cyclin D1 expression and decreased p27 level has also been shown . Consistent with the role of SRC in inducing cyclin D1 gene (CCND1) expression at the transcriptional level (Sinibaldi et al, 2000), we observed a significant CCND1 mRNA downregulation in MSTO-211H and REN cells treated with SI83 and SI91 for 72 h (Figure 3e), which was confirmed also at the protein level (Figure 3f). Conversely, no significant alterations in cyclin D1 expression were observed in MET-5A non-tumoral cells (Figures 3e and f).…”

Section: Src Inhibition Increases P27 Nuclear Localizationsupporting

confidence: 84%

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

et al. 2011

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Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no effective curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo [3,4-d]pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclindependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a wellestablished adverse prognostic factor in MM, and p27 nuclear localization is crucial for its tumor-suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy.

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Section: Src Inhibition Increases P27 Nuclear Localizationsupporting

confidence: 84%

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

et al. 2011

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“…3C). Since expression of cyclin D1, Bcl-xL and Survivin required positive transcriptional control of STAT3 [30,31], the observed changes in these levels were expected. In contrast, levels of anti-apoptotic protein XIAP did not notably decrease after RSV treatment in LU1205.…”

Section: Signaling Pathways Affected By Rsv In Lu1205 Melanoma Cellsmentioning

confidence: 92%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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“…45 The genes that mediate the proliferative effects of STATs include the D and E type cyclins, the cdk inhibitor p21, and the transcription factor c-myc. 19,28,42,[46][47][48][49] The pro-angiogenic effects of STAT3 are likely to be mediated through upregulation of VEGF. 34,35 STAT3 regulation of matrix metalloproteinase-2 (mmp-2) correlates with invasiveness of melanoma cells, 38 and activation of mmp-9 is required for STAT3-induced transformation of mammary epithelial cells.…”

Section: Stat Signaling and Cancermentioning

confidence: 99%

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

Alvarez

Frank²

2004

Cancer Biology & Therapy

104

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Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling

Cited by 264 publications

References 68 publications

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

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