Regulation of FasL by NF-κB and AP-1 in Fas-dependent thymineless death of human colon carcinoma cells

Franklin G. Harwood, Shailaja Kasibhatla, I. Peták, Reka Vernes, Douglas R. Green, Janet A. Houghton

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Cell death due to thymine (dThd) deficiency, associated with the cytotoxic action of 5-fluorouracil in colon cancer, is regulated in thymidylate synthase-deficient (TS-) human colon carcinoma cells via the Fas (CD95, APO-1) death receptor. This was demonstrated by inhibiting the loss in clonogenicity of TS- cells by anti-FasL and in enhanced survival of TS- clones selected for resistance to Fas-mediated apoptosis, following dThd deprivation. During thymineless stress in TS- cells, Fas ligand (FasL) is expressed, and its promoter (hFasLPr) is activated. Transactivation of hFasLPr, dependent upon dThd deficiency, was inhibited following mutation of the binding sites for NF-κB or AP-1 and by preventing NF-κB or AP-1 activation, which inhibited expression of FasL and enhanced clonogenic survival in stable transformants expressing IκBαM or DN-MEKK, respectively. These results demonstrate the crucial roles for NF-κB and AP-1 in the regulation of FasL in Fas-mediated thymineless death of colon carcinoma cells.

Original languageEnglish
Pages (from-to)10023-10029
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number14
DOIs
Publication statusPublished - Apr 7 2000

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Thymidylate Synthase
Fas Ligand Protein
Transcription Factor AP-1
Colon
Cells
Carcinoma
MAP Kinase Kinase Kinases
Death Domain Receptors
Thymine
Cell death
Fluorouracil
Colonic Neoplasms
Transcriptional Activation
Cell Death
Clone Cells
Chemical activation
Binding Sites
Apoptosis
Mutation
Survival

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of FasL by NF-κB and AP-1 in Fas-dependent thymineless death of human colon carcinoma cells. / Harwood, Franklin G.; Kasibhatla, Shailaja; Peták, I.; Vernes, Reka; Green, Douglas R.; Houghton, Janet A.

In: Journal of Biological Chemistry, Vol. 275, No. 14, 07.04.2000, p. 10023-10029.

Research output: Contribution to journalArticle

Harwood, Franklin G. ; Kasibhatla, Shailaja ; Peták, I. ; Vernes, Reka ; Green, Douglas R. ; Houghton, Janet A. / Regulation of FasL by NF-κB and AP-1 in Fas-dependent thymineless death of human colon carcinoma cells. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 14. pp. 10023-10029.
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