Identification of a brain specific protein that associates with a Refsum disease gene product, phytanoyl-CoA alpha-hydroxylase

Lee, Zang Hee; Kim, Hong-Hee; Ahn, Kyu Youn; Seo, Kook Heon; Kim, Jong Keun; Bae, Choon Sang; Kim, Kyung Keun

doi:10.1016/s0169-328x(99)00304-6

Cited by 23 publications

(31 citation statements)

References 24 publications

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“…Phytanoyl-CoA ␣-hydroxylase-associated protein 1 (PAHX-AP1) was isolated as a novel neuron-specific protein that interacts with Refsum disease gene product (PAHX) (6) and the cytoplasmic region of brain-specific angiogenesis inhibitor 1, a seven-span transmembrane protein (7). Refsum disease is an autosomal recessive disorder of lipid metabolism; retinitis pigmentosa and peripheral neuropathy are major clinical findings (8).…”

mentioning

confidence: 99%

A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells

Kim¹,

Jeong²,

Lee³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The transcription of neuron-specific genes must be repressed in nonneuronal cells. REST͞NRSF is a transcription factor that restricts the expression of many neuronal genes through interaction with the neuron-restrictive silencer element at the promoter level. PAHX-AP1 is a neuronal gene that is developmentally up-regulated in the adult mouse brain but that has no functional NRSE motif in its 5 upstream sequence. Here, we report that the transcription factor AP4 and the corepressor geminin form a functional complex in which SMRT and histone deacetylase 3 are recruited. The functional complex represses PAHX-AP1 expression in nonneuronal cells and participates in regulating the developmental expression of PAHX-AP1 in the brain. This complex also serves as a transcriptional repressor of DYRK1A, a candidate gene for Down's syndrome. Furthermore, compared with that in normal fetal brain, the expression of AP4 and geminin is reduced in Down's syndrome fetal brain at 20 weeks of gestation age, at which time premature overexpression of dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) is observed. Our findings indicate that AP4 and geminin act as a previously undescribed repressor complex distinct from REST͞NRSF to negatively regulate the expression of target genes in nonneuronal cells and suggest that the AP4 -geminin complex may contribute to suppressing the precocious expression of target genes in fetal brain.

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confidence: 99%

A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells

Kim¹,

Jeong²,

Lee³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…PAHX has been reported to interact with the blood coagulation factor VIII; it has been proposed that PAHX regulates the expression of this coagulation factor (12), potentially in an oxygen-dependent manner. A further PAHX interaction partner, PAHX-associated protein 1 (PAHX-AP1), identified by a yeast two-hybrid screen (13), interacts with the brainspecific angiogenesis inhibitor 1 (10,14), suggesting a mechanism for some of the neurological symptoms of RD. The physiological significance of these PAHX interactions has not been determined, and how they occur given the apparent peroxisomal localization of PAHX is unclear.…”

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confidence: 99%

Structure of Human Phytanoyl-CoA 2-Hydroxylase Identifies Molecular Mechanisms of Refsum Disease*

McDonough

Kavanagh

Butler

et al. 2005

Journal of Biological Chemistry

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Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid. Many cases of RD are associated with mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial ␣-oxidation step in the degradation of phytenic acid in peroxisomes. We describe the x-ray crystallographic structure of PAHX to 2.

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“…The RNA was purified by centrifugation through 5.7 M CsCl as described [4]. RNA samples were quantitated by spectrophotometry at 260 nm.…”

Section: Northern Blot Analysesmentioning

confidence: 99%

“…The probes used were a 1250-bp NotI-EcoRV fragment (5 0 portion) derived from the lacZ cDNA and a part of BAI1-AP4 cDNA (nucleotide residues 1-415). Probes were radiolabeled by nick translation and hybridizations and signal visualizations were performed as described [4]. The integrity of the RNA samples was established by Northern blot analysis with a mouse GAPDH or b-actin probe.…”

Section: Northern Blot Analysesmentioning

confidence: 99%

“…Previously, brain-specific angiogenesis inhibitor 1-associated protein 4 (BAI1-AP4) was isolated as a novel brain-specific protein that interacted with the Refsum disease gene product and BAI1 [4,5]. In situ hybridization analyses of the brain showed specific localization of BAI1-AP4 to the supragranular layer in the cerebral cortex, hippocampus, dentate gyrus (DG), Purkinje cell layer, and neuronal layers of the retina.…”

Section: Introductionmentioning

confidence: 99%

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The promoter of brain-specific angiogenesis inhibitor 1-associated protein 4 drives developmentally targeted transgene expression mainly in adult cerebral cortex and hippocampus

KIM¹

2004

FEBS Letters

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Restricting transgene expression to specific cell types and maintaining long-term expression are major goals for gene therapy. Previously, we cloned brain-specific angiogenesis inhibitor 1-associated protein 4 (BAI1-AP4), a novel brain-specific protein that interacts with BAI1, and found that it was developmentally upregulated in the adult brain. In this report, we isolated 5 kb of the 5 0 upstream sequence of the mouse BAI1-AP4 gene and analyzed its promoter activity. Functional analyses demonstrated that an Sp1 site was the enhancer, and the region containing the transcription initiation site and an AP2-binding site was the basal promoter. We examined the ability of the BAI1-AP4 promoter to drive adult brain-specific expression by using it to drive lacZ expression in transgenic (TG) mice. Northern blot analyses showed a unique pattern of bgalactosidase expression in TG brain, peaking at 1 month after birth, like endogenous BAI1-AP4. Histological analyses demonstrated the same localization and developmental expression of b-galactosidase and BAI1-AP4 in most neurons of the cerebral cortex and hippocampus. Our data indicate that TG mice carrying the BAI1-AP4 promoter could be a valuable model system for region-specific brain diseases.

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Identification of a brain specific protein that associates with a Refsum disease gene product, phytanoyl-CoA alpha-hydroxylase

Cited by 23 publications

References 24 publications

A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells

A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells

Structure of Human Phytanoyl-CoA 2-Hydroxylase Identifies Molecular Mechanisms of Refsum Disease*

The promoter of brain-specific angiogenesis inhibitor 1-associated protein 4 drives developmentally targeted transgene expression mainly in adult cerebral cortex and hippocampus

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