Protein phosphatase 2A regulates apoptosis in intestinal epithelial cells

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

Research output: Contribution to journalArticle

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Abstract

Polyamine depletion prevents apoptosis by increasing serine/threonine phosphorylation leading to either inactivation or activation of pro- and anti-apoptotic proteins, respectively. Despite evidence that protein kinases are regulators of apoptosis, a specific role for protein phosphatases in regulating cell survival has not been established. In this study, we show that polyamine depletion inhibits serine/threonine phosphatase 2A (PP2A). Inhibition of PP2A in cells depleted of polyamines correlated well with increased phosphorylation of Bad at Ser112. Bad Ser112 phosphorylation in response to tumor necrosis factor (TNF)-α treatment decreased with time in cells grown in control as well as those grown in the presence of α- difluoromethylornithine plus putrescine. However, a sustained increase in the levels of Bad Ser112 phosphorylation was maintained in response to TNF-α treatment in cells grown in the presence of α- difluoromethylornithine. Inhibition of PP2A by okadaic acid and fostriecin or PP2A small interfering HNA transfection significantly decreased TNFα-induced apoptosis in control and polyamine-depleted cells. Inhibition of PP2A by okadaic acid: 1) increased Bad and Bcl-2 phosphorylation at Ser 112 and Ser70, respectively, 2) increased ERK activity; 3) prevented JNK activation; 4) prevented cytochrome c release, and activation of caspases-9 and -3 in response to TNF-α. Inhibition of MEK1 by U0126 prevented phosphorylation of Bad at Ser112. These results indicate that polyamines regulate PP2A activity, and inhibition of PP2A in response to polyamine depletion increases steady state levels of Bad and Bcl-2 proteins and their phosphorylation and thereby prevents cytochrome c release, caspase-9, and caspase-3 activation.

Original languageEnglish (US)
Pages (from-to)31091-31100
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number35
DOIs
StatePublished - Sep 2 2005

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Protein Phosphatase 2
Phosphorylation
Polyamines
Phosphoric Monoester Hydrolases
Epithelial Cells
Apoptosis
Tumor Necrosis Factor-alpha
Chemical activation
Eflornithine
Okadaic Acid
Caspase 9
Phosphoprotein Phosphatases
Cells
Cytochromes c
Caspase 3
Apoptosis Regulatory Proteins
Putrescine
Threonine
Protein Kinases
Serine

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Protein phosphatase 2A regulates apoptosis in intestinal epithelial cells. / Ray, Ramesh M.; Bhattacharya, Sujoy; Johnson, Leonard R.

In: Journal of Biological Chemistry, Vol. 280, No. 35, 02.09.2005, p. 31091-31100.

Research output: Contribution to journalArticle

Ray, Ramesh M. ; Bhattacharya, Sujoy ; Johnson, Leonard R. / Protein phosphatase 2A regulates apoptosis in intestinal epithelial cells. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 35. pp. 31091-31100.
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