Biochemical and Genetic Studies on CC2D1A, a new NF-κB Activator and a Regulator of Synaptic Functions

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Biochemical and Genetic Studies on CC2D1A, a new NF-κB Activator and a Regulator of Synaptic Functions

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dc.contributor.advisor Chen, Zhijian J. en
dc.creator Zhao, Meng en
dc.date.accessioned 2010-07-12T19:01:13Z en
dc.date.available 2010-07-12T19:01:13Z en
dc.date.issued 2010-05-14 en
dc.identifier.other 795506034 en
dc.identifier.uri http://hdl.handle.net/2152.5/766 en
dc.description.abstract CC2D1A is an evolutionarily conserved gene from worm to human. It belongs to a new protein family with four DM14 domains at the NH2 terminus and a C2 domain at the COOH terminus. The function of this protein family remains largely unknown. CC2D1A has been identified as a new NF-κB activator through a large scale screen of human genes by Matsuda et al. Here I show that the conserved DM14 and C2 domains of CC2D1A are important for NF-κB activation. CC2D1A activates the IKK complex and NF-κB target genes through several key components in the canonical pathway including ubiquitin-conjugating enzyme UBC13, a RING domain ubiquitin ligase TRAF2, a protein kinase TAK1, and an essential regulator of IKK complex, NEMO. CYLD, a deubiquitination enzyme specific for Lysine-63 linked polyubiquitin chains, negatively regulates the activity of CC2D1A. These results suggest that CC2D1A activates NF-κB through the canonical IKK pathway. In an attempt to identify the physiological function of CC2D1A, I generated CC2D1A knockout mice. The KO animals die right after birth apparently due to their inability to breathe. Histological analysis identified no significant anatomical defects. In particular, brain, heart and muscle are normal with regard to morphology. In addition, neuromuscular junction at the diaphragm is formed in the absence of Cc2d1a. Human patients with mutations in the gene suffer from mental retardation, implying that Cc2d1a functions in the central nervous system (CNS). Here I show that Cc2d1a expression is enriched in the brain. Deletion of Cc2d1a impairs synapse maturation and function in cortical neurons. Our study may help understand the molecular basis of some human diseases such as mental retardation. en
dc.language.iso en en
dc.subject.mesh Gene Activation en
dc.subject.mesh NF-kappa B en
dc.subject.mesh DNA-Binding Proteins en
dc.title Biochemical and Genetic Studies on CC2D1A, a new NF-κB Activator and a Regulator of Synaptic Functions en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph.D. en
thesis.degree.discipline Genetics & Development en
thesis.date.available 2012-05-14 en

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