Expression of FADD and cFLIP L balances mitochondrial integrity and redox signaling to substantiate apoptotic cell death

FADD and cFLIP both are pivotal components of death receptor signaling. The cellular signaling of apoptosis accomplished with death receptors and mitochondria follows independent pathways for cell death. FADD and cFLIP both have an important role in the regulation of apoptotic and non-apoptotic func...

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Bibliographic Details
Published in:Molecular and cellular biochemistry 2016-11, Vol.422 (1-2), p.135
Main Authors: Ranjan, Kishu, Pathak, Chandramani
Format: Article
Language:English
Subjects:
Animals
Apoptosis
CASP8 and FADD-Like Apoptosis Regulating Protein - biosynthesis
CASP8 and FADD-Like Apoptosis Regulating Protein - genetics
Fas-Associated Death Domain Protein - biosynthesis
Fas-Associated Death Domain Protein - genetics
Gene Expression Regulation
HEK293 Cells
Humans
Mice
Mitochondria - genetics
Mitochondria - metabolism
NIH 3T3 Cells
Oxidation-Reduction
Signal Transduction
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Summary:FADD and cFLIP both are pivotal components of death receptor signaling. The cellular signaling of apoptosis accomplished with death receptors and mitochondria follows independent pathways for cell death. FADD and cFLIP both have an important role in the regulation of apoptotic and non-apoptotic functions. Dysregulated expression of FADD and cFLIP is associated with resistance to apoptosis in cancer cells. Mitochondria are known to play critical role in maintaining cellular respiration and homeostasis in the cells as well as transduces various signals to determine the fate of cell death. However, involvement of FADD and cFLIP in regulation of mitochondrial integrity and programmed cell death signaling to define the fate of cells remains elusive. In the present study, we explored that, induced expression of FADD challenges the mitochondrial integrity and pulverizes the membrane potential by altering the expression of Bcl-2 and cytochrome c. In contrast, mutant of FADD was unable to affect the mitochondrial integrity. Interestingly, expression of FADD and cFLIP helps to balance redox potential by regulating the anti-oxidant levels. Further, we noticed that, knockdown of cFLIP and induced expression of FADD rapidly accumulate intracellular ROS accompanied by JNK1 activation to substantiate apoptosis. Notably, the ectopic expression of cFLIP resists the sensitivity of cancer cells against apoptosis inducers Etoposide and HA14-1. Altogether, our findings suggest that FADD and cFLIP are important modulators of mitochondrial-associated apoptosis apart from the death receptor signaling.
ISSN:1573-4919