Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression.

Michele Yip-Schneider, A. Lin, D. Barnard, C. J. Sweeney, M. S. Marshall

Research output: Contribution to journalArticle

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Abstract

Activating mutations within the K-ras gene have been found in up to 90% of pancreatic carcinomas. Although multiple Ras effector pathways have been identified, the Raf protein kinases which are upstream regulators of the mitogen-activated protein kinases (MAPK/Erk) are believed to be the primary mitogenic effectors. Constitutive upregulation of this pathway by oncogenic ras is thought to promote cellular transformation. To explore the biological effects of mutated K-ras, we analyzed the Ras signaling pathway in a panel of cell lines derived from human pancreatic carcinomas. We found that despite high levels of Ras-GTP in each cell line expressing mutant K-ras, elevated levels of active Erk1 and Erk2 were not detectable under conditions of exponential growth or serum-starvation. Depending upon the cell line, the block in Erk signaling was observed to occur at either the level of Raf or Erk. Increased levels of active Erk1 and Erk2 were detected in only 2 out of 10 normal tissue-matched primary pancreatic tumors with mutated K-ras. Our results suggest that Erk signaling is not aberrantly upregulated in pancreatic cancers containing oncogenic K-ras mutations. The lack of Erk activation observed in both cell lines and primary tumor tissue suggests that constitutive Erk activation may not be required for tumor maintenance or progression in K-ras transformed pancreatic cells. We hypothesize that other Ras-dependent signaling pathways or an unidentified Raf/Mek-dependent pathway may be important for carcinogenesis in the pancreas. These findings may have important implications for drug treatment strategies which currently target the MAP kinase branch of the Ras signaling pathway.

Original languageEnglish
Pages (from-to)271-279
Number of pages9
JournalInternational Journal of Oncology
Volume15
Issue number2
StatePublished - Aug 1999

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Phosphotransferases
Cell Line
raf Kinases
Mutation
ras Genes
Starvation
Guanosine Triphosphate
Mitogen-Activated Protein Kinases
Tumor Cell Line
Pancreatic Neoplasms
Protein Kinases
Pancreas
Neoplasms
Carcinogenesis
Up-Regulation
Maintenance
Growth
Serum
Pharmaceutical Preparations
Pancreatic Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. / Yip-Schneider, Michele; Lin, A.; Barnard, D.; Sweeney, C. J.; Marshall, M. S.

In: International Journal of Oncology, Vol. 15, No. 2, 08.1999, p. 271-279.

Research output: Contribution to journalArticle

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