Disease relevance of STARD3

• CAB1, GRB-7, and c-ERBB-2 were overexpressed in gastric and esophageal cancer cells in correspondence with the amplification [1].
• MLN64 is a protein that is highly expressed in certain breast carcinomas [2].
• 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 [3].
• Molecular cloning of human GRB-7 co-amplified with CAB1 and c-ERBB-2 in primary gastric cancer [4].

High impact information on STARD3

• This mutant exhibited hypersensitive induction of CAB1, CAB2, and the small subunit of ribulose-1,5-bisphosphate carboxylase (RBCS) promoters in the very low fluence range of red light and a hypersensitive response in hypocotyl growth in continuous red light of higher fluences [5].
• Human metastatic lymph node 64 (MLN64) is a transmembrane protein that shares homology with the cholesterol-binding vertebrate steroid acute regulatory protein (StAR)-related lipid transfer domain (START) and is involved in cholesterol traffic and steroid synthesis [6].
• In contrast to StarD4, expression of StarD5 and MLN64 was not sterol-regulated [7].
• The StAR and MLN64 START domains bind 1 mole of 14C cholesterol per mole of protein in vitro [8].
• Wild-type MLN64 increased pregnenolone secretion in this system 2-fold [2].

Biological context of STARD3

• Analysis of array-based comparative genomic hybridization and expression profiling data indicate that the minimum region of recurrent amplification (i.e., the amplicon "core") at 17q12 includes two other genes, GRB7 and STARD3, which exhibit elevated expression when amplified [9].
• Notably, targeted knockdown of either GRB7 or STARD3 also leads to decreased cell proliferation and cell-cycle progression, albeit to a lesser extent compared with ERBB2 knockdown [9].
• Four new genes (A39, C51, CAB1, and GRB-7) coamplified with c-ERBB-2 were isolated from the enriched cDNA library [1].
• The deduced amino acid sequence of the CAB1 gene had significant homology to the recently discovered steroidogenic acute regulatory protein, StAR, which plays an essential role in cholesterol transport to mitochondria [1].
• Gene amplification of ERBB2, PNMT, and MLN64 significantly correlated with increased mRNA gene expression (P < 0.05) [10].

Anatomical context of STARD3

• Isolation of a candidate gene, CAB1, for cholesterol transport to mitochondria from the c-ERBB-2 amplicon by a modified cDNA selection method [1].
• Bacterially expressed N-218 MLN64 exerts StAR-like activity to promote the transfer of cholesterol from the outer to inner mitochondrial membrane in vitro [11].
• We tested the ability of MLN64 to stimulate steroidogenesis by using COS-1 cells cotransfected with plasmids expressing the human cholesterol side-chain cleavage enzyme system and wild-type and mutant MLN64 proteins [2].
• In this study, we show that MLN64 overexpression also induces the formation of enlarged endosomes, an effect that is probably mediated by the MENTAL domain [12].
• Here, we show that MLN64 depletion results in the dispersion of late endocytic organelles to the cell periphery similarly as upon pharmacological actin disruption [13].

Associations of STARD3 with chemical compounds

• CD spectroscopy indicates that N-218 MLN64 is largely alpha-helical and minimally affected by changes in ionic strength or the hydrophobic character of the solvent, although glycerol increases the beta-sheet content [11].
• However, complementation assays show that MLN64 is not involved in the Niemann Pick C2 disease which, results in cholesterol lysosomal accumulation [14].
• Moreover, glutathione S-transferase pull-down or co-immunoprecipitation experiments demonstrate that this domain mediates homo- and hetero-interaction of MLN64 and MENTHO [12].
• Finally, MLN64 colocalizes with cholesterol and Niemann Pick C1 protein in late endosomes [14].
• No stimulation was observed by N-218 MLN64 or N-62 StAR when 20alpha-hydroxycholesterol was added as substrate for P450scc, confirming that these proteins stimulate P450scc activity by enhancing cholesterol transport [15].

Regulatory relationships of STARD3

• Antiserum to StAR cross-reacts with N-218 MLN64, indicating the presence of similar epitopes in both proteins [11].

Other interactions of STARD3

• NPC2, NPC1 and MLN64 may act in an ordered sequence to sense cholesterol, effect sterol movement, and consequently, influence the process of vesicular trafficking [16].
• In living cells, the expression of paired yellow fluorescent and cyan fluorescent fusion proteins show MENTHO homo-interaction and its interaction with MLN64 [12].
• MLN64 overexpression increased the number of actin and p34-Arc-positive patches on late endosomes, enhanced the fusion of late endocytic organelles in an actin-dependent manner, and stimulated the deposition of sterol in late endosomes harboring the protein [13].

Analytical, diagnostic and therapeutic context of STARD3

• Western blotting shows that MLN64 is proteolytically cleaved in the placenta to a size indistinguishable from N-218 MLN64 [11].
• Amplicon mapping by fluorescence in situ hybridization revealed a minimal common region of amplification containing four highly expressed genes, ERBB2, GRB7, MLN64, and an uncharacterized EST 48582 [17].
• Electron microscopy indicates that MLN64 is restricted to the limiting membrane of late endosomes [14].
• Microinjection or endocytosis of specific antibodies shows that the START domain of MLN64 is cytoplasmic [14].
• Total hip replacement using the cementless "Bio-direct" femoral component and the "CAB 1" self-threading acetabular component [18].

References