A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling.

Children's Memorial Research Center, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA.
C53/LZAP (also named as Cdk5rap3) is a putative tumor suppressor that plays important roles in multiple cell signaling pathways, including DNA damage response and NF-kappaB signaling. Yet how its function is regulated remains largely unclear. Here we report the isolation and characterization of two novel C53/LZAP-interacting proteins, RCAD (Regulator of C53/LZAP and DDRGK1) and DDRGK1 (DDRGK domain-containing protein 1). Our co-immunoprecipitation assays confirmed their interactions, while gel filtration assay indicated that C53/LZAP and RCAD may form a large protein complex. Intriguingly, we found that RCAD knockdown led to dramatic reduction of C53/LZAP and DDRGK1 proteins. We also found that C53/LZAP and DDRGK1 became more susceptible to the proteasome-mediated degradation in RCAD knockdown cells, whereas their ubiquitination was significantly attenuated by RCAD overexpression. In addition, we found that RCAD, like C53/LZAP, also plays an important role in regulation of NF-kappaB signaling and cell invasion. Taken together, our findings strongly suggest that RCAD is a novel regulator of C53/LZAP tumor suppressor and NF-kappaB signaling.
Mesh Terms:
Base Sequence, Blotting, Northern, Cell Line, Tumor, Chromatography, Gel, DNA Primers, Gene Knockdown Techniques, Humans, Intracellular Signaling Peptides and Proteins, Microscopy, Electron, NF-kappa B, Nerve Tissue Proteins, Polymerase Chain Reaction, Signal Transduction
J. Biol. Chem. May. 14, 2010; 285(20);15126-36 [PUBMED:20228063]
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