Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells

Kirill Rosen, Janusz Rak, Jing Jin, Robert S. Kerbel, Michael J. Newman, Jorge Filmus*

*Corresponding author for this work

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Anoikis is a form of programmed cell death induced in normal epithelial cells by detachment from the extracellular matrix. In epithelial cells of the intestine and other organs, activated ras induces resistance to anoikis, but the actual molecular effectors directly involved in the apoptotic machinery that execute or block anoikis have not yet been identified. Bak, a pro-apoptotic member of the Bcl-2 family, is downregulated in a high proportion of colorectal tumours. In addition, Bak is an important regulator of apoptosis in normal intestinal epithelial cells. Here, we show that activated ras induces the downregulation of Bak in rat and human intestinal epithelial cells. This ras-induced downregulation of Bak expression could be suppressed by an inhibitor of phosphatidylinositol (PI) 3-kinase, an enzyme already implicated in ras-induced resistance to anoikis. Ectopic expression of Bak in ras-transformed rat intestinal epithelial IEC-18 cells inhibited ras-induced resistance to anoikis and significantly reduced their tumorigenicity. We conclude, therefore, that the ability of ras to downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epithelial cells.

Original languageEnglish (US)
Pages (from-to)1331-1334
Number of pages4
JournalCurrent Biology
Volume8
Issue number24
StatePublished - Dec 3 1998

Fingerprint

Anoikis
Apoptosis Regulatory Proteins
epithelial cells
Down-Regulation
Epithelial Cells
induced resistance
Rats
apoptosis
Phosphatidylinositol 3-Kinase
oncogenes
rats
phosphatidylinositol 3-kinase
Cell death
colorectal neoplasms
extracellular matrix
Machinery
Tumors
Oncogenes
intestines
Intestines

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Rosen, Kirill ; Rak, Janusz ; Jin, Jing ; Kerbel, Robert S. ; Newman, Michael J. ; Filmus, Jorge. / Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells. In: Current Biology. 1998 ; Vol. 8, No. 24. pp. 1331-1334.
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Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells. / Rosen, Kirill; Rak, Janusz; Jin, Jing; Kerbel, Robert S.; Newman, Michael J.; Filmus, Jorge.

In: Current Biology, Vol. 8, No. 24, 03.12.1998, p. 1331-1334.

Research output: Contribution to journalArticle

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T1 - Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells

AU - Rosen, Kirill

AU - Rak, Janusz

AU - Jin, Jing

AU - Kerbel, Robert S.

AU - Newman, Michael J.

AU - Filmus, Jorge

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AB - Anoikis is a form of programmed cell death induced in normal epithelial cells by detachment from the extracellular matrix. In epithelial cells of the intestine and other organs, activated ras induces resistance to anoikis, but the actual molecular effectors directly involved in the apoptotic machinery that execute or block anoikis have not yet been identified. Bak, a pro-apoptotic member of the Bcl-2 family, is downregulated in a high proportion of colorectal tumours. In addition, Bak is an important regulator of apoptosis in normal intestinal epithelial cells. Here, we show that activated ras induces the downregulation of Bak in rat and human intestinal epithelial cells. This ras-induced downregulation of Bak expression could be suppressed by an inhibitor of phosphatidylinositol (PI) 3-kinase, an enzyme already implicated in ras-induced resistance to anoikis. Ectopic expression of Bak in ras-transformed rat intestinal epithelial IEC-18 cells inhibited ras-induced resistance to anoikis and significantly reduced their tumorigenicity. We conclude, therefore, that the ability of ras to downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epithelial cells.

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