STAT3-mediated transcription of Bcl-2, Mcl-1 and C-IAP2 prevents apoptosis in polyamine-depleted cells

Sujoy Bhattacharya, Ramesh M. Ray, Leonard R. Johnson

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

Activation of STAT3 (signal transducer and activator of transcription 3) plays a crucial role in cell survival and proliferation. The aim of the present study was to clarify the role of STAT3 signalling in the protection of polyamine-depleted intestinal epithelial cells against TNF-α (tumour necrosis factor-α)-induced apoptosis. Polyamine depletion by DFMO (α-difluoromethylornithine) caused phosphorylation of STAT3 at Tyr-705 and Ser-727. Phospho-Tyr-705 STAT3 was immunolocalized at the cell periphery and nucleus, whereas phospho-Ser-727 STAT3 was predominantly detected in the nucleus of polyamine-depleted cells. Sustained phosphorylation of STAT3 at tyrosine residues was observed in polyamine-depleted cells after exposure to TNF-α Inhibition of STAT3 activation by AG490 or cell-membrane-permeant inhibitory peptide (PpYLKTK; where pY represents phospho-Tyr) increased the sensitivity of polyamine-depleted cells to apoptosis. Expression of DN-STAT3 (dominant negative-STAT3) completely eliminated the protective effect of DFMO against TNF-α-induced apoptosis. Polyamine depletion increased mRNA and protein levels for Bcl-2, Mcl-1 (myeloid cell leukaemia-1) and C-IAP2 (inhibitor of apoptosis protein-2). Significantly higher levels of Bcl-2 and C-IAP2 proteins were observed in polyamine-depleted cells before and after 9 h of TNF-α treatment. Inhibition of STAT3 by AG490 and DN-STAT3 decreased Bcl-2 promoter activity. DN-STAT3 decreased mRNA and protein levels for Bcl-2, Mcl-1 and C-IAP2 in polyamine-depleted cells. siRNA (small interfering RNA)-mediated inhibition of Bcl-2, Mcl-1 and C-IAP2 protein levels increased TNF-α-induced apoptosis. DN-STAT3 induced the activation of caspase-3 and PARP [poly(ADP-ribose) polymerase] cleavage in polyamine-depleted cells. These results suggest that activation of STAT3 in response to polyamine depletion increases the transcription and subsequent expression of anti-apoptotic Bcl-2 and IAP family proteins and thereby promotes survival of cells against TNF-α-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)335-344
Number of pages10
JournalBiochemical Journal
Volume392
Issue number2
DOIs
StatePublished - Dec 1 2005

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STAT3 Transcription Factor
Myeloid Leukemia
Polyamines
Myeloid Cells
Transcription
Apoptosis
Tumor Necrosis Factor-alpha
Inhibitor of Apoptosis Proteins
Chemical activation
Eflornithine
Phosphorylation
Cell Survival
Cells
Messenger RNA
Proteins
Poly(ADP-ribose) Polymerases
Cell membranes
Cell Nucleus
Caspase 3
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

STAT3-mediated transcription of Bcl-2, Mcl-1 and C-IAP2 prevents apoptosis in polyamine-depleted cells. / Bhattacharya, Sujoy; Ray, Ramesh M.; Johnson, Leonard R.

In: Biochemical Journal, Vol. 392, No. 2, 01.12.2005, p. 335-344.

Research output: Contribution to journalArticle

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abstract = "Activation of STAT3 (signal transducer and activator of transcription 3) plays a crucial role in cell survival and proliferation. The aim of the present study was to clarify the role of STAT3 signalling in the protection of polyamine-depleted intestinal epithelial cells against TNF-α (tumour necrosis factor-α)-induced apoptosis. Polyamine depletion by DFMO (α-difluoromethylornithine) caused phosphorylation of STAT3 at Tyr-705 and Ser-727. Phospho-Tyr-705 STAT3 was immunolocalized at the cell periphery and nucleus, whereas phospho-Ser-727 STAT3 was predominantly detected in the nucleus of polyamine-depleted cells. Sustained phosphorylation of STAT3 at tyrosine residues was observed in polyamine-depleted cells after exposure to TNF-α Inhibition of STAT3 activation by AG490 or cell-membrane-permeant inhibitory peptide (PpYLKTK; where pY represents phospho-Tyr) increased the sensitivity of polyamine-depleted cells to apoptosis. Expression of DN-STAT3 (dominant negative-STAT3) completely eliminated the protective effect of DFMO against TNF-α-induced apoptosis. Polyamine depletion increased mRNA and protein levels for Bcl-2, Mcl-1 (myeloid cell leukaemia-1) and C-IAP2 (inhibitor of apoptosis protein-2). Significantly higher levels of Bcl-2 and C-IAP2 proteins were observed in polyamine-depleted cells before and after 9 h of TNF-α treatment. Inhibition of STAT3 by AG490 and DN-STAT3 decreased Bcl-2 promoter activity. DN-STAT3 decreased mRNA and protein levels for Bcl-2, Mcl-1 and C-IAP2 in polyamine-depleted cells. siRNA (small interfering RNA)-mediated inhibition of Bcl-2, Mcl-1 and C-IAP2 protein levels increased TNF-α-induced apoptosis. DN-STAT3 induced the activation of caspase-3 and PARP [poly(ADP-ribose) polymerase] cleavage in polyamine-depleted cells. These results suggest that activation of STAT3 in response to polyamine depletion increases the transcription and subsequent expression of anti-apoptotic Bcl-2 and IAP family proteins and thereby promotes survival of cells against TNF-α-induced apoptosis.",
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