The Steroidogenic Acute Regulatory Protein Homolog MLN64, a Late Endosomal Cholesterol-binding Protein

Alpy, Fabien; Stoeckel, M. E.; Dierich, Andrée; Escola, Jean-Michel; Wendling, Corinne; Chenard, Marie–Pierre; Vanier, Marie T.; Grüenberg, Jean; Tomasetto, Catherine; Rio, Marie‐Christine

doi:10.1074/jbc.m006279200

Cited by 159 publications

(197 citation statements)

References 42 publications

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“…One important problem has been the lack of information regarding the mechanism by which neurosteroids are synthesized de novo. In the absence of evidence for the presence of StAR, some reports proposed a role for the ubiquitous, peripheral-type benzodiazepine receptor (PBR) (Papadopoulos et al, 1992) or the StAR homolog ML N64 (Watari et al, 1997), a late endosomal protein with unknown f unction (Moog-L utz et al, 1997;Tsujishita and Hurley, 2000;Alpy et al, 2001). The fact remains, however, that only StAR has been unequivocally demonstrated as essential for the regulated delivery of cholesterol to the steroidogenic complex (Stocco and C lark, 1996;Stocco, 2001).…”

Section: Discussionmentioning

confidence: 99%

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

Manna²,

et al. 2002

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Recent data implicate locally produced steroids, termed neurosteroids, as regulators of neuronal function. Adrenal and gonadal steroidogenesis is controlled by changes in the steroidogenic acute regulatory protein (StAR); however, little is known about the regulation of neurosteroid production. We now demonstrate unequivocally that StAR mRNA and protein are expressed within glia and neurons in discrete regions of the mouse brain, and that glial StAR expression is inducible. Consistent with a role in de novo neurosteroidogenesis, StAR colocalizes with the cholesterol side-chain cleavage enzyme P450 scc in both mouse and human brains. These data support a role for StAR in the production of neurosteroids and identify potential sites of active de novo steroid synthesis in the brain.

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Section: Discussionmentioning

confidence: 99%

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

Manna²,

et al. 2002

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“…MLN64 cDNA encodes a protein of 445 residues that can be divided into two domains. The amino-terminal half of the protein contains four potential transmembrane regions and targets the protein to the membrane of late endosomes (Alpy et al, 2001). Recently, we have isolated a novel late-endosomal protein, MENTHO (MLN64 N-terminal domain homologue), structurally related to the amino-terminal half of MLN64.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the region conserved between StAR and MLN64, the StAR-related transfer (START) domain was shown to be a cholesterol-binding domain for both proteins (Tsujishita and Hurley, 2000). While StAR acts as a sterol-carrier directly on the mitochondria (King et al, 1995;Arakane et al, 1998), MLN64 is involved in the cholesterol transport from endosome to cytoplasmic acceptor(s) (Alpy et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors

et al. 2003

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MLN64, is invariably coamplified and coexpressed with erbB-2 in breast cancers. The human MLN64 and ERBB2 genes are positioned at less than 50 kb from each other, on chromosome 17q12. To understand the molecular basis of MLN64 overexpression in cancer, the genomic region containing the MLN64 and ERBB2 genes was isolated and mapped. The two genes, DARPP32 and Telethonin, flanking MLN64 respectively on its centromeric and telomeric sides, although coamplified, are not overexpressed in breast cancer cells, indicating that gene amplification is not sufficient to allow overexpression. The MLN64 minimal promoter was isolated and found to be a housekeeping gene promoter containing four potential Sp1 binding elements. Using Sp1-deficient Drosophila SL2 cells, MLN64 promoter activity was induced in a dosedependent manner by exogenous Sp1 addition. Furthermore, mutation of each individual Sp1 element resulted in a significant decrease in reporter gene activity, indicating that all the Sp1 binding elements are functional and act together to promote gene expression. Since the ERBB2 promoter is also positively regulated by Sp1, this study indicates that MLN64 and ERBB2 genes share common transcriptional controls together with a physical link on chromosome 17q. We speculate that, in addition to the oncogenic potential of erbB-2 overexpression, the unbalanced action of MLN64 contributes to the poor clinical outcome of breast tumors bearing this amplified region.

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“…MLN64 was localized to late endosomes, a cellular compartment involved in the trafficking of cholesterol (15,16). The predicted topology of MLN64 in this compartment has the START domain facing the cytoplasm, being anchored to the vesicle wall by the four transmembrane domains, which positions the START domain to interact with apposing organelles or possibly other START domain proteins in the cytoplasm (16).…”

mentioning

confidence: 99%

“…The predicted topology of MLN64 in this compartment has the START domain facing the cytoplasm, being anchored to the vesicle wall by the four transmembrane domains, which positions the START domain to interact with apposing organelles or possibly other START domain proteins in the cytoplasm (16). MLN64 is incorporated into this dynamic tabulating vesicular system that also contains NPC1, a protein with a sterol-sensing domain (17,18), and NPC2 (also known as HE1), a sterolbinding protein (19).…”

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confidence: 99%

Targeted Mutation of the MLN64 START Domain Causes Only Modest Alterations in Cellular Sterol Metabolism

Kishida

Kostetskii

Zhang

et al. 2004

Journal of Biological Chemistry

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The StAR-related lipid transfer (START) domain, first identified in the steroidogenic acute regulatory protein (StAR), is involved in the intracellular trafficking of lipids. Sixteen mammalian START domain-containing proteins have been identified to date. StAR, a protein targeted to mitochondria, stimulates the movement of cholesterol from the outer to the inner mitochondrial membranes, where it is metabolized into pregnenolone in steroidogenic cells. MLN64, the START domain protein most closely related to StAR, is localized to late endosomes along with other proteins involved in sterol trafficking, including NPC1 and NPC2, where it has been postulated to participate in sterol distribution to intracellular membranes. To investigate the role of MLN64 in sterol metabolism, we created mice with a targeted mutation in the Mln64 START domain, expecting to find a phenotype similar to that in humans and mice lacking NPC1 or NPC2 (progressive neurodegenerative symptoms, free cholesterol accumulation in lysosomes). Unexpectedly, mice homozygous for the Mln64 mutant allele were viable, neurologically intact, and fertile. No significant alterations in plasma lipid levels, liver lipid content and distribution, and expression of genes involved in sterol metabolism were observed, except for an increase in sterol ester storage in mutant mice fed a high fat diet. Embryonic fibroblast cells transfected with the cholesterol side-chain cleavage system and primary cultures of granulosa cells from Mln64 mutant mice showed defects in sterol trafficking as reflected in reduced conversion of endogenous cholesterol to steroid hormones. These observations suggest that the Mln64 START domain is largely dispensable for sterol metabolism in mice.

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The Steroidogenic Acute Regulatory Protein Homolog MLN64, a Late Endosomal Cholesterol-binding Protein

Abstract: MLN64 is a transmembrane protein that shares homology with the cholesterol binding domain (START

Cited by 159 publications

References 42 publications

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors

Targeted Mutation of the MLN64 START Domain Causes Only Modest Alterations in Cellular Sterol Metabolism

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