Article

Nuclear localization of c-FLIP-L and its regulation of AP-1 activity.

Jiangsu Center of Hepatobiliary Diseases and the State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Gulou Hospital, School of Life Sciences, Nanjing University, Nanjing, China.
The international journal of biochemistry & cell biology (impact factor: 4.89). 41(8-9):1678-84. DOI:10.1016/j.biocel.2009.02.008 pp.1678-84
Source: PubMed

ABSTRACT Cellular FLICE-like inhibitory protein (c-FLIP-L), similar in structure to caspase-8, is capable of blocking Fas- or other death receptors (DR)-mediated apoptosis through association with FADD in the DISC. Recent studies have implicated the function of c-FLIP-L in T-cell proliferation, but the exact mechanism underlying this process remains to be elucidated. In this report, we showed for the first time that c-FLIP-L was present in both the cytoplasm and nucleus of cells, but was more abundantly distributed in the nucleus. The putative NLS signal locates within the p12 region of caspase-like domain. Furthermore, c-FLIP's export to cytoplasm membrane was dependent on apoptotic stimulation, while it rapidly translocated to the nucleus in response to proliferative stimuli. To gain insights into the possible function of c-FLIP-L in the nucleus, we found c-FLIP-L could activate the AP-1 transcriptional activity independent of MAPK activation. In sum, our findings describe a novel function of c-FLIP-L involved in AP-1 activation and cell proliferation.

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    Article: c-Flip overexpression affects satellite cell proliferation and promotes skeletal muscle aging.
    C Giampietri, S Petrungaro, P Coluccia, F Antonangeli, K Giannakakis, T Faraggiana, A Filippini, G Cossu, E Ziparo
    [show abstract] [hide abstract]
    ABSTRACT: This study shows that forcing c-Flip overexpression in undifferentiated skeletal myogenic cells in vivo results in early aging muscle phenotype. In the transgenic mice, adult muscle histology, histochemistry and biochemistry show strong alterations: reduction of fibers size and muscle mass, mitochondrial abnormalities, increase in protein oxidation and apoptosis markers and reduced AKT/GSK3β phosphorylation. In the infant, higher levels of Pax-7, PCNA, P-ERK and active-caspase-3 were observed, indicating enhanced proliferation and concomitant apoptosis of myogenic precursors. Increased proliferation correlated with NF-κB activation, detected as p65 phosphorylation, and with high levels of embryonic myosin heavy chain. Reduced regenerative potential after muscle damage in the adult and impaired fiber growth associated with reduced NFATc2 activation in the infant were also observed, indicating that the satellite cell pool is prematurely compromised. Altogether, these data show a role for c-Flip in modulating skeletal muscle phenotype by affecting the proliferative potential of undifferentiated cells. This finding indicates a novel additional mechanism through which c-Flip might possibly control tissue remodeling.
    Cell Death & Disease 04/2010; 1:e38. · 5.33 Impact Factor
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Keywords

AP-1 transcriptional activity independent
 
apoptotic stimulation
 
c-FLIP's export
 
c-FLIP-L
 
capable
 
cell proliferation
 
Cellular FLICE-like inhibitory protein
 
DR)-mediated apoptosis
 
Fas-
 
gain insights
 
MAPK activation
 
p12 region
 
proliferative stimuli
 
putative NLS signal locates
 
Recent studies
 
T-cell proliferation