| 1. |
- Do, Hai Thi, et al.
(författare)
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Reciprocal Regulation of Very Low Density Lipoprotein Receptors (VLDLRs) in Neurons by Brain-derived Neurotrophic Factor (BDNF) and Reelin INVOLVEMENT OF THE E3 LIGASE Mylip/Idol
- 2013
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Ingår i: Journal of Biological Chemistry. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0021-9258 .- 1083-351X. ; 288:41, s. 29613-29620
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Tidskriftsartikel (refereegranskat)abstract
- BDNF positively influences various aspects of neuronal migration, maturation, and survival in the developing brain. Reelin in turn mediates inhibitory signals to migrating neuroblasts, which is crucial for brain development. The interplay between BDNF and Reelin signaling in neurodevelopment is not fully understood. We show here that BDNF increased the levels of the Reelin receptor (VLDL receptor (VLDLR)) in hippocampal neurons by increasing gene expression. In contrast, Reelin decreased VLDLRs, which was accompanied by an increase in the levels of the E3 ligase Mylip/Idol in neurons. Down-regulation of Mylip/Idol using shRNAs abrogated the decrease in VLDLRs induced by Reelin. These results show that VLDLRs are tightly regulated in hippocampal neurons by both transcriptional and post-transcriptional mechanisms. The regulation of VLDLR by BDNF and Reelin may affect the migration of neurons and contribute to neurodevelopmental disorders in the nervous system.
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| 2. |
- Hong, Cynthia, et al.
(författare)
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The E3 Ubiquitin Ligase IDOL Induces the Degradation of the Low Density Lipoprotein Receptor Family Members VLDLR and ApoER2
- 2010
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Ingår i: Journal of Biological Chemistry. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0021-9258 .- 1083-351X. ; 285:26, s. 19720-19726
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor ( LDLR) ( Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism.
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