A nuclear function of Hu proteins as neuron-specific alternative RNA processing regulators.
Recent advances in genome-wide analysis of alternative splicing indicate that extensive alternative RNA processing is associated with many proteins that play important roles in the nervous system. Although differential splicing and polyadenylation make significant contributions to the complexity of the nervous system, our understanding of the regulatory mechanisms underlying the neuron-specific pathways is very limited. Mammalian neuron-specific embryonic lethal abnormal visual-like Hu proteins (HuB, HuC, and HuD) are a family of RNA-binding proteins implicated in neuronal differentiation and maintenance. It has been established that Hu proteins increase expression of proteins associated with neuronal function by up-regulating mRNA stability and/or translation in the cytoplasm. We report here a novel function of these proteins as RNA processing regulators in the nucleus. We further elucidate the underlying mechanism of this regulation. We show that in neuron-like cells, Hu proteins block the activity of TIA-1/TIAR, two previously identified, ubiquitously expressed proteins that promote the nonneuronal pathway of calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA processing. These studies define not only the first neuron-specific regulator of the calcitonin/CGRP system but also the first nuclear function of Hu proteins.
Zhu
Hui
H
Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Hasman
Robert A
RA
Barron
Victoria A
VA
Luo
Guangbin
G
Lou
Hua
H
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002116:Calcitonin / Q000235:genetics; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D009928:Organ Specificity; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D011485:Protein Binding; D012322:RNA Precursors / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D000074019:T-Cell Intracellular Antigen-1; D014529:Uridine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D039102:Poly(A)-Binding Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C076751:TIAL1 protein, human; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide; D014529:Uridine