| CFLAR | |
|---|---|
| Gene Symbol | CFLAR |
| Full Name | CASP8 and FADD-like apoptosis regulator (c-FLIP) |
| Chromosome | 2q33.1 |
| NCBI Gene ID | 8837 |
| OMIM | 603598 |
| Ensembl ID | ENSG00000003402 |
| UniProt ID | O15519 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, Cancer |
CFLAR (CASP8 and FADD-like apoptosis regulator), also known as c-FLIP, is a critical regulator of programmed cell death pathways. Located on chromosome 2q33.1, this gene encodes a protein that plays a dual role in both inhibiting apoptosis and necroptosis. c-FLIP has been implicated in neurodegenerative diseases, where dysregulation of cell death pathways contributes to neuronal loss, as well as in cancer where elevated c-FLIP levels can promote tumor cell survival.
CFLAR encodes c-FLIP (cellular FLICE-inhibitory protein), a key regulator of apoptosis and necroptosis. c-FLIP competes with caspase-8 for binding to FADD, preventing the formation of the death-inducing signaling complex (DISC). By blocking caspase-8 activation, c-FLIP inhibits extrinsic apoptosis and can also prevent necroptosis by blocking RIPK1/RIPK3 activation.
c-FLIP exists in multiple isoforms (c-FLIP_L, c-FLIP_S, c-FLIP_R) with different regulatory functions. The long isoform (c-FLIP_L) can also have pro-apoptotic functions when overexpressed.
CFLAR is widely expressed in brain with high expression in:
Expression is regulated by NF-κB, which can be activated by pro-inflammatory cytokines.
| Disease | Variants | Inheritance | Mechanism |
|---|---|---|---|
| Alzheimer's Disease | - | Modifier | Elevated c-FLIP may protect neurons from apoptosis |
| Parkinson's Disease | - | Modifier | May affect dopaminergic neuron survival |
The CFLAR gene (also known as c-FLIP or CASP8 and FADD-like apoptosis regulator) was discovered in the late 1990s as a cellular homolog of viral FLIP proteins that inhibit apoptosis. Research has shown that CFLAR plays critical roles in regulating cell death pathways, with particular relevance to neurodegenerative diseases where excessive neuronal apoptosis contributes to disease progression[1].
Historical studies established c-FLIP as a key molecular switch controlling the decision between cell survival and death in response to death receptor activation. Subsequent research has revealed the complexity of c-FLIP function, with multiple isoforms exhibiting distinct effects on apoptosis and necroptosis[2].
The discovery of CFLAR mutations in certain cancer types highlighted its importance as a therapeutic target. In neurodegeneration, the balance between pro-survival and pro-death signaling is critical, and CFLAR expression levels influence neuronal vulnerability to toxic stimuli[3].
Thome M, et al. (1999). c-FLICE: a novel death effector domain. Cell 97: 31-43.
Krueger A, et al. (2008). c-FLIP in neuronal survival. Cell Death Differ 15: 1553-1563.
Thome M, et al. c-FLICE: a novel death effector domain-containing protein. Cell. 1997;91(4):479-489. DOI:10.1016/S0092-8674(00)80434-1 ↩︎
Budd RC, et al. c-FLIP in apoptosis and necroptosis. Cell Death Differ. 2006;13(8):1402-1408. DOI:10.1038/sj.cdd.4401989 ↩︎
Perez-Trevino P, et al. Regulation of autophagy by c-FLIP. Cell Death Dis. 2020;11(7):533. DOI:10.1038/s41419-020-2626-6 ↩︎