Source:http://linkedlifedata.com/resource/pubmed/id/18288467
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
4
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pubmed:dateCreated |
2008-4-18
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pubmed:abstractText |
We recently identified the Phafin protein family, whose members all contain an N-terminal PH domain (pleckstrin homology) and a C-terminal FYVE (Fab1, YGLO23, Vps27, and EEA1) domain. LAPF (lysosome-associated apoptosis-inducing protein containing PH and FYVE domains, also known as Phafin-1), as one representative member of this new family, has been shown to be able to initiate caspase-independent apoptosis through lysosomal-mitochondrial apoptotic pathway. Here, we describe the cloning and functional characterization of another Phafin member, EAPF (endoplasmic reticulum-associated apoptosis-involved protein containing PH and FYVE domains)/Phafin-2. Overexpression of EAPF/Phafin-2 enhances the sensitivity of L929 and MCF-7 cells to TNF-alpha-induced apoptosis, concomitant with its partial translocation to endoplasmic reticulum (ER). Both the PH and the FYVE domains contribute to the ER translocation of EAPF/Phafin-2 as well as EAPF/Phafin-2-enhanced apoptosis. Knockdown of mouse and human EAPF/Phafin-2 expression protects L929 cells and MCF-7 cells from TNF-alpha-induced apoptosis, respectively. We demonstrate that EAPF/Phafin-2 induces a much sharper and more rapid Ca2+ influx triggered by TNF-alpha and Ca2+ release ER contributes to the enhancement of EAPF/Phafin-2 in TNF-induced apoptosis. EAPF/Phafin-2 increases the activity of caspase 12, suggesting that EAPF/Phafin-2 is involved in ER-related apoptotic pathway. Overexpression of EAPF/Phafin-2 also enhances TNF-alpha-induced activity of caspase 3 (but not caspase 8 or 9), and promotes TNF-alpha-triggered mitochondrial membrane permeabilization (MMP) in L929 cells, including dissipation of mitochondrial membrane potential and release of AIF. Besides, EAPF/Phafin-2 also suppresses the unfolded protein response by inhibiting phosphorylation of eIF2alpha. Therefore, our results demonstrate that EAPF/Phafin-2 facilitates TNF-alpha-induced cellular apoptosis through an ER-mitochondrial apoptotic pathway, which may improve our understanding of drug-induced cancer cell death and cancer chemotherapy.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0946-2716
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
86
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
471-84
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pubmed:dateRevised |
2011-7-8
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pubmed:meshHeading |
pubmed-meshheading:18288467-Amino Acid Sequence,
pubmed-meshheading:18288467-Animals,
pubmed-meshheading:18288467-Apoptosis,
pubmed-meshheading:18288467-Apoptosis Regulatory Proteins,
pubmed-meshheading:18288467-Calcium,
pubmed-meshheading:18288467-Caspases,
pubmed-meshheading:18288467-Cell Line,
pubmed-meshheading:18288467-Endoplasmic Reticulum,
pubmed-meshheading:18288467-Enzyme Activation,
pubmed-meshheading:18288467-Humans,
pubmed-meshheading:18288467-Mice,
pubmed-meshheading:18288467-Mitochondria,
pubmed-meshheading:18288467-Molecular Sequence Data,
pubmed-meshheading:18288467-Recombinant Fusion Proteins,
pubmed-meshheading:18288467-Sequence Alignment,
pubmed-meshheading:18288467-Tissue Distribution,
pubmed-meshheading:18288467-Tumor Necrosis Factor-alpha
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pubmed:year |
2008
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pubmed:articleTitle |
EAPF/Phafin-2, a novel endoplasmic reticulum-associated protein, facilitates TNF-alpha-triggered cellular apoptosis through endoplasmic reticulum-mitochondrial apoptotic pathway.
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pubmed:affiliation |
Institute of Immunology, Zhejiang University, Hangzhou 310031, People's Republic of China.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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