C/EBPα or C/EBPα oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-κB p50 bound to the ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-02

AUTHORS

A D Friedman, A K Ghosal, I Paz-Priel, J Kowalski

ABSTRACT

CCAAT/enhancer-binding protein alpha (C/EBPalpha) is mutated in 10% of acute myeloid leukemias, resulting in either a truncated protein or an altered leucine zipper (C/EBPalphaLZ) that prevents DNA binding. C/EBPalpha induces bcl-2 in cooperation with nuclear factor-kappaB (NF-kappaB) p50 to inhibit apoptosis. We now demonstrate that C/EBPalpha or a C/EBPalphaLZ oncoprotein binds the bcl-2 P2 promoter in chromatin immunoprecipitation assays and induces the promoter dependent on the integrity of a kappaB site. C/EBPalpha expressed as a transgene in B cells binds and activates the bcl-2 promoter, but not in nfkb1-/- mice lacking NF-kappaB p50. Bcl-2 is central to the intrinsic apoptotic pathway, whereas FLICE inhibitory protein (FLIP) modulates caspase-8, the initiator caspase of the extrinsic pathway. C/EBPalpha and C/EBPalphaLZ also bind the FLIP promoter and induce its expression dependent upon NF-kappaB p50. Moreover, induction of FLIP by C/EBPalpha protects splenocytes from Fas ligand-induced apoptosis, but only if p50 is present. We also demonstrate the direct interaction between bacterially produced C/EBPalpha and NF-kappaB p50, mediated by the C/EBPalpha basic region. These findings indicate that C/EBPalpha or its oncoproteins activate the bcl-2 and FLIP genes by tethering to their promoters through bound NF-kappaB p50. Targeting their interaction may favor apoptosis of transformed cells. More... »

PAGES

365

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2008.297

DOI

http://dx.doi.org/10.1038/leu.2008.297

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1015392050

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18987666


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