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The role of CARMA2/CARD14 in NF-kB activation signalling

The caspase recruitment domain (CARD)-containing proteins CARMA1-3 share high degree of sequence, structure and functional homology. Whereas CARMA1 and CARMA3 have been identified as crucial components of signal trasduction pathways that lead to activation of NF-kB transcription factor, little is known about the function of CARMA2. Here we report the identification of two splice variants of CARMA2. One transcript, named CARMA2short (CARMA2sh), is predicted to encode for a CARMA2 polypeptide containing the CARD, coiled coil and a PDZ domains, but lacking the SH3 and the GuK domains. The second variant, CARMA2cardless (CARMA2cl), encodes for a polypeptide lacking the CARD domain and containing only a portion of the coiled coil domain and a linker region. Expression analysis confirmed the presence of the CARMA2 alternatively spliced transcripts in both human cell lines and tissues. Fluorescence microscopy data show that both splice variants localize in the cytosol. Biochemical experiments indicate that CARMA2sh interacts with TRAF2 and activates NF-kB in a TRAF2-dependent manner.

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3 1 Introduction 1.1)Nuclear Factor – kB (NF-kB) 1.1.1) Structural and functional aspects The eukaryotic transcription factor NF-kB (nuclear factor kappa-light-chain- enhancer of activated B-cells) was identified as a protein that bound to a specific decameric DNA sequence, within the intronic enhancer of the immunoglobulin kappa light chain in mature B- cells and plasma cells but not pre B-cells (Sen and Baltimore, 1986, Cell). Later, it was demonstrated that NF-kB DNA binding activity is induced by a variety of exogeneous stimuli, and that this activation is independent from de-novo protein synthesis. NF –kB has been detected in most cells type and his binding sites has been found on a lot of promoters and enanchers of inducible genes. NF –kB is found in almost all animal cell types and it is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiations, oxidized LDL, and bacterial or viral antigens. NF-kB plays a key role in regulating the immune response to infection. Conversely, incorrect regulation of NF -kB has been linked to cancer (it promote the proliferation and represses the apoptosis so could be up – expressed in cancer cells), inflammatory and autoimmune diseases, septic shock, viral infections and improper immune development. The term NF –kB indicate a large family of protein that include the NF- kB proteins and the REL proteins. All of these proteins share a highly conserved DNA-binding/dimerization domain called the Rel homology domain (RHD), because these N-terminal 300 aa revealed high similarity to the viral oncoprotein v-Rel, which human cellular homologue is c-Rel and the orthologue one is Drosophila’s protein Dorsal. Moreover RHD contains the nuclear localization

Laurea liv.II (specialistica)

Facoltà: Scienze Matematiche, Fisiche e Naturali

Autore: Francesco Morra Contatta »

Composta da 41 pagine.

 

Questa tesi ha raggiunto 1272 click dal 12/04/2011.

Disponibile in PDF, la consultazione è esclusivamente in formato digitale.