Mini-reviewFLIP: A flop for execution signals
Highlights
āŗ Resistance to death receptor induced apoptosis. āŗ cFLIP expression induces death resistance. āŗ cFLIP as a target for anti-cancer drug development.
Introduction
Escape from normal constraints on growth and proliferation, genomic instability, and resistance to apoptosis are among the hallmarks of cancer [1]. The latter is a function of up regulation of proteins that block apoptosis at different stages of the death execution program. Indeed, a tilt in the intracellular ratio of death promoting proteins and death inhibitory proteins in favor of the latter provides cells with a survival advantage resulting in aberrant proliferation and setting the stage for transformation. Therefore, the past three decades have seen a tremendous increase in interest in understanding the molecular mechanisms underlying the regulation of gene expression, as well as functional biology of the anti-apoptotic effector mechanisms/pathways operative in neoplasia. These efforts have provided insights into novel signaling networks and their regulatory nodes, particularly from the standpoint of genes/proteins that control cell fate decisions.
Section snippets
Apoptosis is a natural tumor suppressor mechanism
Deregulation of apoptotic machinery by suppression and/or decreased expression of pro-apoptotic molecules and/or increased levels of pro-survival proteins is an essential requirement for cancer initiation and progression [2]. Therefore, novel anti-cancer strategies include drugs that reactivate death signaling by specifically targeting anti-apoptotic proteins such as Bcl-2 [3], IAP family [4] and cFLIP (FLICE inhibitory protein [5].
Apoptotic cell death is classified into extrinsic and intrinsic
cFLIP promotes carcinogenesis by regulating apoptotic signaling
The cellular FLICE-inhibitory protein (cFLIP; also referred to as Casper, FLAME-1, CLARP) is the mammalian homolog of the viral cell death regulatory proteins v-FLIPs, and expressed in three different isoforms, namely cFLIPL (55Ā kDa), cFLIPR (24Ā kDa) and cFLIPs (26Ā kDa) [10], [11]. It should be pointed out that the expression of the various isoforms is a function of alternative splicing of the cFLIP gene, which is transcribed under the same promoter. Of note, despite structural differences at the
Genome organization and regulation of cFLIP expression
The genome organization of cFLIP is quite complex as the gene is 50Ā Kb in length and spatially separated by 10 introns. The promoter region spans about 1.5Ā Kb upstream of the transcriptional start site and contains numerous transcription factorsā binding sites [16]. Among the several possible transcription factors associated with the activation of cFLIP transcription are AP-1 (c-Fos and c-Jun), CREB, SP1, and NF-kB [10]. In addition, other transcription factor binding sites have been described
Cross talk between cell metabolism and cFLIP
Although, the major point of focus has been the death inhibitory activity of cFLIP, in particular its ability to inhibit death receptor-mediated signaling, recent evidence points to a complex network of pathways involved in the regulation of cFLIP as well as the effect of cFLIP expression on cellsā metabolic activity. For example, the intricate crosstalk between NF-kB signaling and cFLIP expression underscores the importance of this protein in the workings of a āmasterā regulator of cell
Concluding remarks and unanswered questions
Overexpression of cFLIP isoforms is associated with resistance to death receptor and drug-induced apoptosis. Therefore, targeting cFLIP has been proposed as an attractive strategy for novel anti-cancer drug design. Thus, use of siRNA mediated gene silencing and identification of compounds with the ability to down-regulate cFLIP expression are attractive and logical options. In this regard, a number of small molecule compounds have been shown to sensitize cancer cells via their effect on the
Acknowledgements
We would like to acknowledge all authors whose work may have been omitted due to space constraint. S.P. is supported by grants from The National Medical Research Council, The Biomedical Research Council, The Ministry of Education (Tier 2), and the Cancer Science institute, Singapore. Special thanks to Dr. Gregory Mellier for assistance in preparing the schematic illustration.
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