2003 Fiscal Year Final Research Report Summary
The Role of RNA Binding Protein Hu in pathophysiology of the paraneoplastic neurologic disorders (PND's)
| Project/Area Number |
14570615
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | KEIO UNIVERSITY |
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Principal Investigator |
OKANO Hirotaka james Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (90338020)
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| Co-Investigator(Kenkyū-buntansha) |
OKANO Hideyuki Keio University, School of Medicine, Professor, 医学部, 教授 (60160694)
AKAMATSU Wado Keio University, School of Medicine, Assistant, 医学部, 助手 (60338184)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Hu / RNA binding protein / paraneoplastic neurologic disorders / p27Kip1 / translational control / IRES dependent translation / neural differentiation |
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| Research Abstract |
The paraneoplastic neurologic disorders (PND's) are neurologic diseases occurring in the setting of non-neuronal tumors that express neuronal antigens. The expression of such "onconeural" antigens in tumor cells is thought to induce an immune response which suppresses tumor growth, but causes neuronal degeneration. Hu proteins are mammalian ELAV-like neuronal RNA-binding proteins that were identified as autoimmune antigens of PND. Recently, we provided evidence that mHuB and mHuC are required for and capable of inducing neuronal phenotype in both CNS and PNS. In vitro RNA selection experiments identified RNAs harboring UGUUUGU elements to which Hu proteins bound with sequence-specificity and high affinity. Furthermore, we found that Hu binds to UGUUUGU element present in 5'UTR of p27KIP1 mRNA to regulate Cap-dependent and IRES-dependent translation. Next we have used genetic and biochemical analyses to determine that Hu proteins induce neuronal differentiation by regulating the metabolism of specific target mRNAs. Several findings support the idea that Hu proteins may undergo protein-protein interactions in addition to RNA binding. To examine whether Hu interacts specifically with other proteins, and to assess whether these interactions might modulate the ability of Hu to regulate translation, we have performed biochemical purification experiments using flag tagged Hu-recombinant adenovirus. We identified 6 proteins at least, including hnRNPK, NF45, and SKB1 that are expressed in the brain and interact with Hu in vitro. To determine in vivo functions of Hu, we generated HuD null and HuB null mice. Although HuD null mice are born phenotypically normal, one third of the animals show a progressive motor deficit and die in the first months of postnatal life. In contrast, HuB null mice are embryonic lethal with developmental abnormalities in cortex. Our results demonstrate that HuB is essential for terminal differentiation in developing neurons.
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