Adenomatous polyposis coli, protein kinases, protein tyrosine phosphatase

The effect of sulindac

W. R. Waddell, Roger Miesfeld

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A putative explanation of the effect of sulindac on adenomatous colon and duodenal polyps from clinical observations and related in vitro experiments is presented. In cells with mutant APC genes, persistent high prostaglandin content of polyps leads to desensitization, downregulation of adenylate cyclase, uncoupling of cAMP synthesis from prostaglandin, and inactivation of protein kinase A (PKA). It is suggested that in normal cells, (APC) protein binds to catenins and microtubules to maintain structure and contribute to cell-cell communication, adherence, and the dephosphorylated state, a necessary condition for such functions. Cells with mutant APC product become isolated, deprived of communication and adhesion to other epithelial cells, overphosphorylated, and without corrective capability. The latter is largely due tn downregulation of cAMP synthesis and protein kinase A activity secondary tn high prostaglandin. Three main biochemical defects ensue: (1) the restrictive influence of PKA catalyzed phosphorylation of Raf-1 kinase and resultant effects on the MAP kinase cascade and transcription is lost, (2) the transcription of immediate early genes, including cyclooxygenase is stimulated, and (3) the stimulation of protein tyrosine phosphatase (PTPase) by PKA is in abeyance. These putative abnormalities are reversed by inhibition of cyclooxygenase-1 by sulindac. cAMP synthesis and PKA activity return to normal. PKA catalyzed phosphorylations block Raf-1 kinase at the confluence of the Ras and protein kinase C pathways. The MAP kinase cascade is inhibited as is transcription of immediate early genes. At the same time PKA stimulates PTPase, which dephosphorylates the cytoskeleton and restores cell-cell communication, adherence, and structure. The transformed phenotype is circumvented by adjustment of the phosphorylation state and mutant cells rejoin the epithelial community. The redox state of cytoplasm in mutant cells may be shifted toward reduction.

Original languageEnglish (US)
Pages (from-to)252-256
Number of pages5
JournalJournal of Surgical Oncology
Volume58
Issue number4
StatePublished - 1995

Fingerprint

Adenomatous Polyposis Coli Protein
Sulindac
Protein Tyrosine Phosphatases
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
Proto-Oncogene Proteins c-raf
Prostaglandins
Immediate-Early Genes
MAP Kinase Signaling System
Phosphorylation
Polyps
Cell Communication
Down-Regulation
Epithelial Cells
APC Genes
ras Proteins
Catenins
Cyclooxygenase 1
Prostaglandin-Endoperoxide Synthases
Cytoskeleton

Keywords

  • tyrosine kinase and phosphatase

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Adenomatous polyposis coli, protein kinases, protein tyrosine phosphatase : The effect of sulindac. / Waddell, W. R.; Miesfeld, Roger.

In: Journal of Surgical Oncology, Vol. 58, No. 4, 1995, p. 252-256.

Research output: Contribution to journalArticle

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