PTEN and TNF-α regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-κB-dependent pathway

Sunghoon Kim, Claire Domon-Dell, Qingding Wang, Dai H. Chung, Antonio Di Cristofano, Pier Paolo Pandolfi, Jean Noel Freund, B. Mark Evers

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Background & Aims: PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a dual-specificity phosphatase implicated in embryonic development, intestinal cell proliferation and differentiation, and tumor suppression. The transcription factor Cdx-2 is critical in intestinal development and homeostasis, and its expression is altered in colorectal cancers. However, the regulation of the Cdx-2 gene has not been entirely elucidated. Here, we hypothesize that Cdx-2 may be a target of PTEN signaling in the intestine. Methods: The expression patterns for Cdx-2 and PTEN along wild-type mouse colon, as well as in colon tumors occurring in Pten+/- mice, were examined. The effect of PTEN or phosphatidylinositol 3-kinase inhibition and tumor necrosis factor α on Cdx-2 messenger RNA and protein expression, Cdx-2 DNA binding activity, and the promoter activity of the Cdx-2 gene was analyzed in human colon cancer cell lines. Results: Cdx-2 expression correlates with PTEN along the length of the murine colon and in colonic polyps that develop in Pten+/- mice. In colon cancer cells, PTEN stimulates Cdx-2 protein expression and the transcriptional activity of the Cdx-2 promoter. Phosphatidylinositol 3-kinase inhibition by wortmannin or by a dominant-negative phosphatidylinositol 3-kinase mimics the Cdx-2 stimulation by PTEN. Inversely, cell treatment by tumor necrosis factor α decreases Cdx-2 expression. Phosphatidylinositol 3-kinase inhibition by PTEN or wortmannin has an inverse effect compared with tumor necrosis factor α on the balance between the p50 and p65 subunits of nuclear factor κB. p65 inhibits the activity of the Cdx-2 promoter, whereas p50 prevents p65 action. Conclusions: Our results suggest that the intestinal Cdx-2 homeobox gene is a target of PTEN/phosphatidylinositol 3-kinase signaling and tumor necrosis factor α signaling via nuclear factor κB-dependent pathways.

Original languageEnglish (US)
Pages (from-to)1163-1178
Number of pages16
JournalGastroenterology
Volume123
Issue number4
DOIs
StatePublished - Oct 1 2002
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Homeobox Genes
Phosphatidylinositol 3-Kinases
Tumor Necrosis Factor-alpha
Colon
Colonic Neoplasms
Dual-Specificity Phosphatases
PTEN Phosphohydrolase
Colonic Polyps
Chromosomes, Human, Pair 10
Genes
Intestines
Embryonic Development
Cell Differentiation
Colorectal Neoplasms
Neoplasms
Homeostasis
Transcription Factors
Cell Proliferation
Cell Line

ASJC Scopus subject areas

  • Gastroenterology

Cite this

PTEN and TNF-α regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-κB-dependent pathway. / Kim, Sunghoon; Domon-Dell, Claire; Wang, Qingding; Chung, Dai H.; Di Cristofano, Antonio; Pandolfi, Pier Paolo; Freund, Jean Noel; Evers, B. Mark.

In: Gastroenterology, Vol. 123, No. 4, 01.10.2002, p. 1163-1178.

Research output: Contribution to journalArticle

Kim, Sunghoon ; Domon-Dell, Claire ; Wang, Qingding ; Chung, Dai H. ; Di Cristofano, Antonio ; Pandolfi, Pier Paolo ; Freund, Jean Noel ; Evers, B. Mark. / PTEN and TNF-α regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-κB-dependent pathway. In: Gastroenterology. 2002 ; Vol. 123, No. 4. pp. 1163-1178.
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abstract = "Background & Aims: PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a dual-specificity phosphatase implicated in embryonic development, intestinal cell proliferation and differentiation, and tumor suppression. The transcription factor Cdx-2 is critical in intestinal development and homeostasis, and its expression is altered in colorectal cancers. However, the regulation of the Cdx-2 gene has not been entirely elucidated. Here, we hypothesize that Cdx-2 may be a target of PTEN signaling in the intestine. Methods: The expression patterns for Cdx-2 and PTEN along wild-type mouse colon, as well as in colon tumors occurring in Pten+/- mice, were examined. The effect of PTEN or phosphatidylinositol 3-kinase inhibition and tumor necrosis factor α on Cdx-2 messenger RNA and protein expression, Cdx-2 DNA binding activity, and the promoter activity of the Cdx-2 gene was analyzed in human colon cancer cell lines. Results: Cdx-2 expression correlates with PTEN along the length of the murine colon and in colonic polyps that develop in Pten+/- mice. In colon cancer cells, PTEN stimulates Cdx-2 protein expression and the transcriptional activity of the Cdx-2 promoter. Phosphatidylinositol 3-kinase inhibition by wortmannin or by a dominant-negative phosphatidylinositol 3-kinase mimics the Cdx-2 stimulation by PTEN. Inversely, cell treatment by tumor necrosis factor α decreases Cdx-2 expression. Phosphatidylinositol 3-kinase inhibition by PTEN or wortmannin has an inverse effect compared with tumor necrosis factor α on the balance between the p50 and p65 subunits of nuclear factor κB. p65 inhibits the activity of the Cdx-2 promoter, whereas p50 prevents p65 action. Conclusions: Our results suggest that the intestinal Cdx-2 homeobox gene is a target of PTEN/phosphatidylinositol 3-kinase signaling and tumor necrosis factor α signaling via nuclear factor κB-dependent pathways.",
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T1 - PTEN and TNF-α regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-κB-dependent pathway

AU - Kim, Sunghoon

AU - Domon-Dell, Claire

AU - Wang, Qingding

AU - Chung, Dai H.

AU - Di Cristofano, Antonio

AU - Pandolfi, Pier Paolo

AU - Freund, Jean Noel

AU - Evers, B. Mark

PY - 2002/10/1

Y1 - 2002/10/1

N2 - Background & Aims: PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a dual-specificity phosphatase implicated in embryonic development, intestinal cell proliferation and differentiation, and tumor suppression. The transcription factor Cdx-2 is critical in intestinal development and homeostasis, and its expression is altered in colorectal cancers. However, the regulation of the Cdx-2 gene has not been entirely elucidated. Here, we hypothesize that Cdx-2 may be a target of PTEN signaling in the intestine. Methods: The expression patterns for Cdx-2 and PTEN along wild-type mouse colon, as well as in colon tumors occurring in Pten+/- mice, were examined. The effect of PTEN or phosphatidylinositol 3-kinase inhibition and tumor necrosis factor α on Cdx-2 messenger RNA and protein expression, Cdx-2 DNA binding activity, and the promoter activity of the Cdx-2 gene was analyzed in human colon cancer cell lines. Results: Cdx-2 expression correlates with PTEN along the length of the murine colon and in colonic polyps that develop in Pten+/- mice. In colon cancer cells, PTEN stimulates Cdx-2 protein expression and the transcriptional activity of the Cdx-2 promoter. Phosphatidylinositol 3-kinase inhibition by wortmannin or by a dominant-negative phosphatidylinositol 3-kinase mimics the Cdx-2 stimulation by PTEN. Inversely, cell treatment by tumor necrosis factor α decreases Cdx-2 expression. Phosphatidylinositol 3-kinase inhibition by PTEN or wortmannin has an inverse effect compared with tumor necrosis factor α on the balance between the p50 and p65 subunits of nuclear factor κB. p65 inhibits the activity of the Cdx-2 promoter, whereas p50 prevents p65 action. Conclusions: Our results suggest that the intestinal Cdx-2 homeobox gene is a target of PTEN/phosphatidylinositol 3-kinase signaling and tumor necrosis factor α signaling via nuclear factor κB-dependent pathways.

AB - Background & Aims: PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a dual-specificity phosphatase implicated in embryonic development, intestinal cell proliferation and differentiation, and tumor suppression. The transcription factor Cdx-2 is critical in intestinal development and homeostasis, and its expression is altered in colorectal cancers. However, the regulation of the Cdx-2 gene has not been entirely elucidated. Here, we hypothesize that Cdx-2 may be a target of PTEN signaling in the intestine. Methods: The expression patterns for Cdx-2 and PTEN along wild-type mouse colon, as well as in colon tumors occurring in Pten+/- mice, were examined. The effect of PTEN or phosphatidylinositol 3-kinase inhibition and tumor necrosis factor α on Cdx-2 messenger RNA and protein expression, Cdx-2 DNA binding activity, and the promoter activity of the Cdx-2 gene was analyzed in human colon cancer cell lines. Results: Cdx-2 expression correlates with PTEN along the length of the murine colon and in colonic polyps that develop in Pten+/- mice. In colon cancer cells, PTEN stimulates Cdx-2 protein expression and the transcriptional activity of the Cdx-2 promoter. Phosphatidylinositol 3-kinase inhibition by wortmannin or by a dominant-negative phosphatidylinositol 3-kinase mimics the Cdx-2 stimulation by PTEN. Inversely, cell treatment by tumor necrosis factor α decreases Cdx-2 expression. Phosphatidylinositol 3-kinase inhibition by PTEN or wortmannin has an inverse effect compared with tumor necrosis factor α on the balance between the p50 and p65 subunits of nuclear factor κB. p65 inhibits the activity of the Cdx-2 promoter, whereas p50 prevents p65 action. Conclusions: Our results suggest that the intestinal Cdx-2 homeobox gene is a target of PTEN/phosphatidylinositol 3-kinase signaling and tumor necrosis factor α signaling via nuclear factor κB-dependent pathways.

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