Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice

Amy Moran, Daniel H. Hunt, Sara H. Javid, Mark Redston, Adelaide M. Carothers, Monica M. Bertagnolli

Research output: Contribution to journalArticle

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Abstract

Overexpression of the epidermal growth factor receptor (EGFR) and its increased tyrosine kinase activity are implicated in colorectal cancer (CRC) development and malignant progression. The C57BL/6J-Min/+ (Min/+) mouse is a model for CRC and develops numerous intestinal adenomas. We analyzed the normal mucosa of Min/+ and Apc +/+ (WT) littermate mice together with Apc-null adenomas to gain insight into the roles of Egfr in these intestinal tissues. Protein analyses showed that Egfr activity was highest in the tumors, and also up-regulated in Min/+ relative to WT enterocytes. Expression of ubiquitylated Egfr (Egfr-Ub) was increased in Min/+ enterocytes and tumors. Tumors exhibited increased association of Egfr with clathrin heavy chain (CHC), Gab1, and p85α, the regulatory subunit of phosphoinositide 3-kinase (PISK), and tumors also overexpressed c-Src, PDK1, and Akt. Immunohistochemistry for Akt-p-Ser473 revealed a low level of this active kinase in Min/+ and WT enterocytes and its strong presence in tumors. Prostaglandin E 2 (PGE 2) is a product of cyclooxygenase-2 (Cox-2) activity that is up-regulated in Min/+ tumors and transactivates Egfr. PGE 2 expression was significantly higher in untreated Min/+ tumors and reduced by treatment with the Cox-2 inhibitor, celecoxib. Dietary administration of this NSAID also inhibited Egfr activity in tumors. Increased activation of the EGFR-PI3K-Akt signaling pathway in tumors relative to Apc +/+ and Apc Min/+ enterocytes provides potential opportunities for therapeutic interventions to differentially suppress tumor formation, promotion, progression, and/or recurrence.

Original languageEnglish (US)
Pages (from-to)43261-43272
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number41
DOIs
StatePublished - Oct 8 2004
Externally publishedYes

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Enterocytes
Adenoma
Tumors
Neoplasms
Celecoxib
Prostaglandins E
Epidermal Growth Factor Receptor
Colorectal Neoplasms
Clathrin Heavy Chains
Phosphotransferases
1-Phosphatidylinositol 4-Kinase
Cyclooxygenase 2 Inhibitors
Non-Steroidal Anti-Inflammatory Agents
Cyclooxygenase 2
Phosphatidylinositols
Phosphatidylinositol 3-Kinases
Protein-Tyrosine Kinases
Mucous Membrane
Chemical activation
Immunohistochemistry

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice. / Moran, Amy; Hunt, Daniel H.; Javid, Sara H.; Redston, Mark; Carothers, Adelaide M.; Bertagnolli, Monica M.

In: Journal of Biological Chemistry, Vol. 279, No. 41, 08.10.2004, p. 43261-43272.

Research output: Contribution to journalArticle

Moran, Amy ; Hunt, Daniel H. ; Javid, Sara H. ; Redston, Mark ; Carothers, Adelaide M. ; Bertagnolli, Monica M. / Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 41. pp. 43261-43272.
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abstract = "Overexpression of the epidermal growth factor receptor (EGFR) and its increased tyrosine kinase activity are implicated in colorectal cancer (CRC) development and malignant progression. The C57BL/6J-Min/+ (Min/+) mouse is a model for CRC and develops numerous intestinal adenomas. We analyzed the normal mucosa of Min/+ and Apc +/+ (WT) littermate mice together with Apc-null adenomas to gain insight into the roles of Egfr in these intestinal tissues. Protein analyses showed that Egfr activity was highest in the tumors, and also up-regulated in Min/+ relative to WT enterocytes. Expression of ubiquitylated Egfr (Egfr-Ub) was increased in Min/+ enterocytes and tumors. Tumors exhibited increased association of Egfr with clathrin heavy chain (CHC), Gab1, and p85α, the regulatory subunit of phosphoinositide 3-kinase (PISK), and tumors also overexpressed c-Src, PDK1, and Akt. Immunohistochemistry for Akt-p-Ser473 revealed a low level of this active kinase in Min/+ and WT enterocytes and its strong presence in tumors. Prostaglandin E 2 (PGE 2) is a product of cyclooxygenase-2 (Cox-2) activity that is up-regulated in Min/+ tumors and transactivates Egfr. PGE 2 expression was significantly higher in untreated Min/+ tumors and reduced by treatment with the Cox-2 inhibitor, celecoxib. Dietary administration of this NSAID also inhibited Egfr activity in tumors. Increased activation of the EGFR-PI3K-Akt signaling pathway in tumors relative to Apc +/+ and Apc Min/+ enterocytes provides potential opportunities for therapeutic interventions to differentially suppress tumor formation, promotion, progression, and/or recurrence.",
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AU - Carothers, Adelaide M.

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