BALANCE BETWEEN SHORT AND LONG ISOFORMS OF c-FLIP REGULATES Fas-MEDIATED APOPTOSIS IN VIVO.
Abstract: cFLIP has
been thought of to be a crucial regulator of apoptosis and necroptosis. This protein has
been shown to also have roles in development as a deficiency in cFLIP leads to embryonic
lethality in mice at day E10.5. cFlip is a Caspase 8 homologue that predominantly exists
as two isoforms: cFLIPL (long) and cFLIPR (short) in mice. Humans have an additional
short isoform: cFLIPS ... read more- which differs from cFLIPR by the inclusion of a few extra amino
acids in the C-terminus. In isolation - both isoforms have been shown to inhibit Caspase
8 activation, and as a result it has been thought that cFLIP is a crucial inhibitor of
apoptosis. However it has been show recently that the role of cFLIPL¬ is more
nuanced than previously understood, where it may actually play a role in augmenting
apoptotic signaling in the context of its shorter isoform, cFLIPR. In this thesis work I
report the work leading to the description of an underappreciated resistance model to
Fas-mediated liver lethality in the wild-derived inbred MSM/Ms mouse, compared to the
susceptible C57BL/6. I also show that the resistance is associated with the inheritance
of a 21bp insertion in Chromosome 1 within the 3'UTR of cFLIPR in MSM/Ms mice. I
postulate that this 21bp insertion is able to recruit components of the spliceosome and
result in the preferential transcription/translation of cFLIPL in MSM/Ms livers. I show
that this is a liver-specific phenotype, implying the role of tissue-specific factors,
and also show that N5F3 congenic mice, with a predominantly C57BL/6 genetic background
(96% C57BL/6, 4% MSM/Ms) and homozygous for the 21bp MSM insertion, are more resistant
to LPS than their C57BL/6 founder strain.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Immunology.
Advisor: Alexander Poltorak.
Committee: Brigitte Huber, Stephen Bunnell, and Henry Wortis.
Keywords: Immunology, and Genetics.read less