Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation

Young Youl Kim, Bum Joon Park, Gill Ju Seo, Joong Yeon Lim, Sang Min Lee, Kyu Chan Kimm, Chan Park, Joon Kim, Sang Ick Park

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Since Fas-induced apoptosis is major pathway to eliminate unwanted or uncontrolled cells, many types of human cancer cells develop tactful mechanisms to get resistance against the apoptosis. One of the resistant mechanisms in human cancer is overexpression of FLICE-inhibitory protein (c-FLIP), human homolog of viral protein v-FLIP. c-FLIP has multiple splice variants at transcriptional level or two isoforms at protein level, a long (c-FLIP L) and a short form of c-FLIP (c-FLIPS). However, functional differences between these variants are not fully understood. In this study, we show that c-FLIPL but not c-FLIPS physically binds to Daxx through interaction between C-terminal domain of c-FLIP L and Fas-binding domain of Daxx, an alternative Fas signaling adaptor. Fas-induced cell death and JNK activation are sensitive to Fas stimulation in cell lines carrying undetectable level of c-FLIPL. To support this, overexpression of c-FLIPL but not of c-FLIP S renders the cells resistant to Fas-induced cell death and to JNK activation. In signaling context, the interaction of c-FLIPL with Daxx is likely to inhibit JNK activation by preventing the normal interaction of Daxx and Fas, which is known to lead to apoptosis via JNK activation. This study implies that through this new mechanism, c-FLIPL, acting at both FADD- and Daxx-mediated signaling pathways, may be involved in complete inhibition of Fas-induced cell death and may provide an answer to why c-FLIPL is more abundant and effective than c-FLIPS.

Original languageEnglish
Pages (from-to)426-433
Number of pages8
JournalBiochemical and biophysical research communications
Volume312
Issue number2
DOIs
Publication statusPublished - 2003 Dec 12

Keywords

  • Apoptosis
  • C-FLIP
  • Daxx
  • Fas
  • JNK

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation'. Together they form a unique fingerprint.

  • Cite this