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PubMed1997

Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2).

Sterol-regulatory element binding protein (SREBP) 1 and SREBP2 are ubiquitously expressed transcription factors that play key roles in the regulation of cholesterol and fatty acid metabolism. SREBP1 and SREBP2 share approximately 47% sequence identity and map to chromosomes 17 and 22, respectively. The gene encoding SREBP1 (SREBF1) has been cloned and characterized. In this paper we describe the gene structure and 5'-flanking sequence of SREBF2. SREBF2 spans 72 kb and is composed of 19 exons and 18 introns. The locations of the exon/intron boundaries of SREBF2 are remarkably similar to those of SREBF1, but SREBF2 is approximately 2.8 times larger in size. The 5'-flanking regions of SREBF2 and of two alternatively spliced forms of SREBF1, SREBF1a and SREBF1c, were sequenced, and the SREBF2 transcription start site was determined. A perfect 10-bp sterol regulatory element (SRE)-1 sequence was present in the promoter region of SREBF2. No SRE-1 was identified in the 5'-flanking sequences of either SREBF1a or SREBF1c, but several E-box sequences were present in SREBP1c. Thus, analysis of the 5'-flanking regions provides support that these two transcription factors, though similar in their coding sequence and overall gene structure, have different physiological roles. Finally, evidence is presented for the presence of another expressed gene of unknown function located 500 bp upstream of SREBF2.

Amino Acid Sequence↗

PubMed2002

Expression of a novel, sterol-insensitive form of sterol regulatory element binding protein 2 (SREBP2) in male germ cells suggests important cell- and stage-specific functions for SREBP targets during spermatogenesis.

Cholesterol biosynthesis in somatic cells is controlled at the transcriptional level by a homeostatic feedback pathway involving sterol regulatory element binding proteins (SREBPs). These basic helix-loop-helix (bHLH)-Zip proteins are synthesized as membrane-bound precursors, which are cleaved to form a soluble, transcriptionally active mature SREBP that regulates the promoters for genes involved in lipid synthesis. Homeostasis is conferred by sterol feedback inhibition of this maturation process. Previous work has demonstrated the expression of SREBP target genes in the male germ line, several of which are highly up-regulated during specific developmental stages. However, the role of SREBPs in the control of sterol regulatory element-containing promoters during spermatogenesis has been unclear. In particular, expression of several of these genes in male germ cells appears to be insensitive to sterols, contrary to SREBP-dependent gene regulation in somatic cells. Here, we have characterized a novel isoform of the transcription factor SREBP2, which is highly enriched in rat and mouse spermatogenic cells. This protein, SREBP2gc, is expressed in a stage-dependent fashion as a soluble, constitutively active transcription factor that is not subject to feedback control by sterols. These findings likely explain the apparent sterol-insensitive expression of lipid synthesis genes during spermatogenesis. Expression of a sterol-independent, constitutively active SREBP2gc in the male germ line may have arisen as a means to regulate SREBP target genes in specific developmental stages. This may reflect unique roles for cholesterol synthesis and other functional targets of SREBPs during spermatogenesis.

Amino Acid Sequence↗

PubMed2004

Impaired regulation of sterol regulatory element binding protein 2 in cholesterol gallstone-susceptible mice.

Lipid synthesis is under tight transcriptional control involving sterol regulatory element binding proteins (SREBP1, SREBP2). Rising cellular cholesterol levels prevent SREBP2 from entering the nucleus to directly activate the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr), the key enzyme of cholesterol synthesis. The failure to down-regulate cholesterol synthesis in gallstone-susceptible C57L/J but not AKR/J mice prompted us to study the processing of SREBP2 in these mice. Male mice of each strain received a control or lithogenic diet for 28 days. Membrane and nuclear extracts of pooled livers were prepared for immunoblot analysis of SREBP. Steady-state mRNA levels of Hmgcr, Srebp1, Srebp2 and the SREBP cleavage activating protein (Scap) were measured from individual livers. There was no marked difference between the two strains with regard to processing of SREBP1 as well as steady-state mRNA levels of Srebp1, Srebp2 and Scap. However, a near-complete suppression of nuclear SREBP2 related to low Hmgcr mRNA levels was noticed only for gallstone-resistant AKR mice. Abnormal regulation of SREBP2 appears to be responsible for the failure to suppress cholesterol synthesis in genetically cholesterol gallstone-susceptible mice. This defect may contribute to cholesterol hypersecretion and gallstone formation.

Animals↗

PubMed2006

Androgen regulation of prostasin gene expression is mediated by sterol-regulatory element-binding proteins and SLUG.

BACKGROUND: Prostasin is downregulated in hormone-refractory prostate cancers (HRPC). The mechanisms by which androgens regulate prostasin expression are unclear. METHODS: LNCaP cells were treated with dihydrotestosterone (DHT), and mRNA expression of prostasin, SREBPs, SNAIL, and SLUG was examined by real-time PCR following reverse transcription. A human prostasin promoter was evaluated in HEK-293 cells co-transfected with transcription factor cDNAs. Regulation of endogenous prostasin expression by transfected SREBP-2 or SLUG was evaluated. Expression of SNAIL and SLUG mRNA in DU-145 cells treated with epidermal growth factor (EGF) was examined. RESULTS: Prostasin mRNA expression in LNCaP cells was not responsive to DHT treatment. DHT marginally upregulated mRNA expression of SREBP-1c, SREBP-2, and SNAIL, but not SREBP-1a, while dramatically increased SLUG mRNA expression, in a dose-dependent manner. Co-transfection of prostasin promoter and SREBP cDNA in HEK-293 cells resulted in stimulation of promoter activity at approximately twofold by SREBP-1c, and up to sixfold by SREBP-2; while co-transfection with SNAIL or SLUG cDNA resulted in repression of promoter activity to 43% or 59%, respectively. Co-transfection of the SLUG cDNA negated SREBP-2's stimulation of prostasin promoter in a dose-dependent manner. Transfection of an SREBP-2 cDNA in HEK-293 and DU-145 resulted in upregulation of prostasin while transfection of a SLUG cDNA in LNCaP repressed prostasin expression. EGF upregulated SNAIL and SLUG mRNA in DU-145. CONCLUSIONS: DHT regulates prostasin expression in prostate cells via SREBP stimulation and SLUG repression of prostasin promoter. SLUG is upregulated by DHT and EGF, providing a molecular mechanism by which epithelial cell-specific genes are silenced during prostate cancer development and progression.

Androgens↗

PubMed2006

Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival.

Many pathogenic organisms produce pore-forming toxins as virulence factors. Target cells however mount a response to such membrane damage. Here we show that toxin-induced membrane permeabilization leads to a decrease in cytoplasmic potassium, which promotes the formation of a multiprotein oligomeric innate immune complex, called the inflammasome, and the activation of caspase-1. Further, we find that when rendered proteolytic in this context caspase-1 induces the activation of the central regulators of membrane biogenesis, the Sterol Regulatory Element Binding Proteins (SREBPs), which in turn promote cell survival upon toxin challenge possibly by facilitating membrane repair. This study highlights that, in addition to its well-established role in triggering inflammation via the processing of the precursor forms of interleukins, caspase-1 has a broader role, in particular linking the intracellular ion composition to lipid metabolic pathways, membrane biogenesis, and survival.

Aeromonas↗

PubMed2005

A novel functional interaction between the Sp1-like protein KLF13 and SREBP-Sp1 activation complex underlies regulation of low density lipoprotein receptor promoter function.

Cholesterol homeostasis is regulated by a family of transcription factors designated sterol regulatory element-binding proteins (SREBPs). Precise control of SREBP-targeted genes requires additional interactions with co-regulatory transcription factors. In the case of the low density lipoprotein receptor (LDLR), SREBP cooperates with the specificity protein Sp1 to activate the promoter. In this report, we describe a novel pathway in LDLR transcriptional regulation distinct from the SREBP-Sp1 activation complex involving the Sp1-like protein Krueppel-like factor 13 (KLF13). Using a combination of RNA interference, electrophoretic mobility shift, chromatin immunoprecipitation, and reporter assays, deletion, and site-directed mutagenesis, we demonstrated that KLF13 mediates repression in a DNA context-selective manner. KLF13 repression of LDLR promoter activity appears to be needed to keep the receptor silent, a state that can be antagonized by Sp1, SREBP, and inhibitors of histone deacetylase activity. Chromatin immunoprecipitation assay confirmed that KLF13 binds proximal LDLR DNA sequences in vivo and that exogenous oxysterol up-regulates such binding. Together these studies identify a novel regulatory pathway in which gene repression by KLF13 must be overcome by the Sp1-SREBP complex to activate the LDLR promoter. Therefore, these data should replace a pre-existent and more simple paradigm that takes into consideration only the induction of the activator proteins Sp1-SREBP as necessary for LDLR promoter drive without including default repression, such as that by KLF13, of the LDLR gene.

Animals↗

PubMed2006

A developmental switch in transcription factor isoforms during spermatogenesis controlled by alternative messenger RNA 3'-end formation.

Spermatogeniccells elaborate a highly specialized differentiation program that is mediated in part by germ cell-enriched transcription factors. This includes a novel member of the sterol response element-binding factor family, SREBF2_v1/SREBP2gc. Somatic SREBFs are predominantly synthesized as precursor proteins and are critical regulators of cholesterol and fatty acid synthesis. In contrast, SREBF2_v1 bypasses the precursor pathway and has been directly implicated in spermatogenic cell-specific gene expression. During spermatogenesis, SREBF2 precursor transcripts predominate in premeiotic stages, while SREBF2_v1 is highly upregulated specifically in pachytene spermatocytes and round spermatids. In the present study, we demonstrate thatSrebf2_v1mRNAs are present in the testis of several mammalian species, including humans. The basis for the stage-dependent transition in SREBF2 isoforms was also investigated. A 3' rapid amplification of cDNA ends (RACE)-PCR analysis of the rat and human revealed thatSrebf2_v1transcripts are generated by alternative pre-mRNA cleavage/polyadenylation. This involves the use of an intronic, A(A/U)UAAA-independent poly(A) signal within intron 7 of theSrebf2gene. Developmentally regulated competition between germ cell factors that control RNA splicing and pre-mRNA cleavage/polyadenylation may underlie this process. These results define an important role for alternative polyadenylation in male germ cell gene expression and development by controlling a stage-dependent switch in transcription factor structure and function during spermatogenesis. TheSrebf2gene thus provides a useful model to explore the role of alternative polyadenylation in regulating stage-dependent functions of important protein regulators in spermatogenic cells.

Alternative Splicing↗

PubMed2005

Calorie restriction modulates renal expression of sterol regulatory element binding proteins, lipid accumulation, and age-related renal disease.

Sterol regulatory element binding proteins (SREBP) are major regulators of fatty acid and cholesterol synthesis. This study found that age-related renal matrix deposition and proteinuria were associated with increased renal expression of SREBP-1 and SREBP-2 and increased renal accumulation of triglyceride and cholesterol. Because calorie restriction (CR) modulates age-related renal disease, it then was determined whether the effects of CR are mediated partially by modulation of renal lipid metabolism. Compared with ad libitum (AL)-fed 24-month-old (24 m) F344BN rats, CR resulted in significant decreases in extracellular matrix accumulation (periodic acid-Schiff staining and immunofluorescence of type IV collagen and fibronectin) and proteinuria. A significant decrease was also observed in the renal expression of growth factors (connective tissue growth factor and vascular endothelial growth factor) and matrix metalloproteinase inhibitor (plasminogen activator inhibitor-1). These structural and functional changes were associated with significant decreases in renal nuclear SREBP-1 (5.2 in 24 m AL versus 3.3 densitometry units in 24 m CR; P < 0.01) and SREBP-2 (7.1 in 24 m AL versus 4.1 densitometry units in 24 m CR; P < 0.01) protein abundance and renal triglyceride and cholesterol contents. It is interesting that serum leptin level was significantly increased as a function of aging, and CR resulted in significant reduction in serum leptin level. Because it was shown previously that increased renal expression of SREBP-1a per se caused renal lipid accumulation, glomerulosclerosis, and proteinuria, the results suggest that CR modulates age-related renal disease in part by modulation of renal SREBP expression and renal lipid accumulation.

Aging↗

PubMed2005

Caspase-2, a novel lipid sensor under the control of sterol regulatory element binding protein 2.

Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5'-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels.

5' Flanking Region↗

PubMed2004

Transcription factor sterol regulatory element binding protein 2 regulates scavenger receptor Cla-1 gene expression.

OBJECTIVE: The human scavenger receptor class B type I (Cla-1) plays a key role in cellular cholesterol movement in facilitating transport of cholesterol between cells and lipoproteins. Indirect evidence has suggested that Cla-1 gene expression is under the feedback control of cellular cholesterol content. To define the molecular mechanisms underlying such putative regulation, we evaluated whether Cla-1 is a target gene of the sterol regulatory element binding protein (SREBP) transcription factor family. METHODS AND RESULTS: Transient transfections demonstrated that SREBP factors induce Cla-1 promoter activity and that SREBP-2 is a more potent inducer than the SREBP-1a isoform. The 5'-deletion analysis of 3 kb of the 5'-flanking sequence of the Cla-1 gene, combined with site-directed mutagenesis and electrophoretic mobility shift assay, allowed identification of a unique sterol responsive element. SREBP-mediated Cla-1 regulation was confirmed in stably transfected human embryonic kidney 293 cells expressing the active form of SREBP-2 at incremental levels. In these cell lines, Cla-1 mRNA and protein levels were increased in direct proportion to the level of SREBP-2 expression. CONCLUSIONS: These findings provide evidence that SREBP-2, a key regulator of cellular cholesterol uptake through modulation of the expression of the low-density lipoprotein receptor gene, may influence cellular cholesterol homeostasis via regulation of Cla-1 gene expression.

Binding Sites↗

PubMed2006

Modulation of human Niemann-Pick C1-like 1 gene expression by sterol: Role of sterol regulatory element binding protein 2.

Niemann-Pick C1-like 1 (NPC1L1) is an essential intestinal component of cholesterol absorption. However, little is known about the molecular regulation of intestinal NPC1L1 expression and promoter activity. We demonstrated that human NPC1L1 mRNA expression was significantly decreased by 25-hydroxycholesterol but increased in response to cellular cholesterol depletion achieved by incubation with Mevinolin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) in human intestinal Caco-2 cells. We also showed that a -1741/+56 fragment of the NPC1L1 gene demonstrated high promoter activity in Caco-2 cells that was reduced by 25-hydroxycholesterol and stimulated by cholesterol depletion. Interestingly, we showed that the NPC1L1 promoter is remarkably transactivated by the overexpression of sterol regulatory element (SRE) binding protein (SREBP)-2, suggesting its involvement in the sterol-induced alteration in NPC1L1 promoter activity. Finally, we identified two putative SREs in the human NPC1L1 promoter and established their essential roles in mediating the effects of cholesterol on promoter activity. Our study demonstrated the modulation of human NPC1L1 expression and promoter activity by cholesterol in a SREBP-2-dependent mechanism.

Base Sequence↗

PubMed2004

The effect of sterol regulatory element-binding protein 2 polymorphism on the serum lipid in northern Chinese subjects.

Sterol regulatory element-binding protein 2 (SREBP-2) is an important nuclear transcription factor in the regulation of cellular cholesterol metabolism. To determine allele frequency of the 1784G>C polymorphism at the SREBP-2 locus and investigate the relationship between this polymorphism and serum lipid levels in Chinese people, we selected 486 individuals (118 men and 368 women) from the Xicheng District of Beijing. The subjects were divided into four groups: hypercholesterolemic subjects, hypertriglyceridemic subjects, combined hyperlipidemic subjects, and normal subjects. Serum lipid profiles were measured in all subjects, and 1784G>C was analyzed using polymerase chain reaction-restriction fragment length polymorphism analysis. There was no significant difference in genotype frequencies or allele frequencies of this polymorphism between the hyperlipidemic and control groups. The serum total cholesterol (TC) and LDL cholesterol (LDL-C) levels of the individuals carrying the C allele were higher than the noncarriers in both males and females in the hypercholesterolemic group, but statistical significance was only observed in females. The results of this study indicate that the SREBP-2 polymorphism is related to elevated concentrations of serum TC and LDL-C in hypercholesterolemic subjects. Further work is necessary to confirm the role of 1784G>C in the development of hyperlipidemia.

Adult↗

PubMed2001

Dimerization of sterol regulatory element-binding protein 2 via the helix-loop-helix-leucine zipper domain is a prerequisite for its nuclear localization mediated by importin beta.

The sterol regulatory element-binding protein 2 (SREBP-2), a transcription factor of the basic helix-loop-helix-leucine zipper (bHLH-Zip) family, is synthesized in the form of a membrane-attached precursor molecule. When cells are deprived of sterols, a two-step proteolytic processing releases the transcriptionally active N-terminal segment of SREBP-2, thereby allowing it to enter the nucleus. In previous studies, we showed that the nuclear import of SREBP-2 occurs via the direct interaction of importin beta with the HLH-Zip domain. In this study, in order to more completely understand the intracellular dynamics of SREBP-2, we focused on the manner by which importin beta recognizes SREBP-2 at the initial step of the import. It was found that the active form of SREBP-2 exists as a stable dimer in solution and that the substitution of leucine residues for alanine in the leucine zipper motif disrupted the dimerization. It was also demonstrated that this mutant protein did not enter the nucleus either in vivo or in vitro. Solution binding assays, which involved the chemical cross-linking of wild-type or mutated SREBP-2 with importin beta, revealed that the import-active complex appeared to be composed of a dimeric form of SREBP-2 and importin beta. In addition, the SREBP-2 binding domain of importin beta corresponded to an overlapping but not identical region for importin alpha binding, which may explain how importin beta is able to recognize the dimeric HLH-Zip directly. These results indicate that dimerization is a prerequisite process for the nuclear import of SREBP-2 mediated by importin beta.

Amino Acid Sequence↗

PubMed1995

Independent regulation of sterol regulatory element-binding proteins 1 and 2 in hamster liver.

Two sterol regulatory element-binding proteins (SREBPs, designated SREBP-1 and SREBP-2), each approximately 1150 amino acids in length, are attached to membranes of the endoplasmic reticulum and nuclear envelope in human and hamster tissue culture cells. In the absence of sterols, soluble fragments of approximately 470 amino acids are released from both proteins by proteolytic cleavage. The soluble fragments enter the nucleus, where they bind to sterol regulatory elements in the promoters of genes encoding the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl CoA synthase, thereby activating transcription. Proteolytic processing of both SREBPs is blocked coordinately by sterol overloading and enhanced coordinately when sterols are depleted by treatment with an inhibitor of cholesterol synthesis. In contrast to these findings in cultured cells, the current data show that SREBP-1 and -2 are not coordinately regulated in hamster liver. In untreated animals the soluble fragment of SREBP-1, but not of SREBP-2, was detected by immunoblotting of a liver nuclear extract. Depletion of sterols by treatment with a bile acid-binding resin (colestipol) and a cholesterol synthesis inhibitor (mevinolin) led to a marked increase in the nuclear form of SREBP-2 and a reciprocal decline in the nuclear form of SREBP-1. These findings suggest that SREBP-1 is responsible for basal transcription of the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl CoA synthase genes in hamster liver and that SREBP-2 is responsible for the increased transcription that follows sterol depletion with a bile acid-binding resin and a cholesterol synthesis inhibitor.

Animals↗

PubMed2004

Direct inhibition of the ubiquitin-proteasome pathway by ester bond-containing green tea polyphenols is associated with increased expression of sterol regulatory element-binding protein 2 and LDL receptor.

Green tea has been shown to lower plasma cholesterol, associated with up-regulation of the low-density lipoprotein receptor (LDLR) although the responsible molecular mechanism is unknown. Previously, we reported that ester bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG], potently inhibit the tumor cellular proteasome activity, which may contribute to the cancer-preventative effect of green tea. In the current study, we hypothesize that the proteasome is a heart disease-associated molecular target of GTPs. We have shown that ester bond-containing GTPs, including (-)-EGCG, potently inhibit the proteasomal activity in intact hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cells, as evident by accumulation of ubiquitinated proteins and three natural proteasome targets (p27, IkappaB-alpha and Bax). (-)-EGCG selectively inhibits the chymotrypsin-like, but not trypsin-like, activity of the proteasome. Associated with proteasome inhibition by ester bond-containing GTPs, there was a significant, time- and concentration-dependent increase in levels of the cleaved, activated, but not the precursor, form of sterol regulatory element-binding protein 2 (SREBP-2), an essential factor for LDLR transcription. Subsequently, LDL receptor expression was increased dramatically in HepG2 and HeLa cells treated with (-)-EGCG. Our results suggest that ester bond-containing GTPs inhibit ubiquitin/proteasome-mediated degradation of the active SREBP-2, resulting in up-regulation of LDLR. This identified molecular mechanism may be related to the previously reported cholesterol-lowering and heart disease-preventative effects of green tea.

Camellia sinensis↗

PubMed2001

Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator, SREBP2.

The low-density lipoprotein receptor (LDLR) pathway provides cells with essential fatty acids for prostaglandin E2 (PGE2) synthesis. Regulation of LDLR expression by LDL was compared between the human normal and cancer prostate cells using semi-quantitative RT-PCR and LDL uptake assays. LDLR mRNA expression and LDL uptake by LDLR were down-regulated in the presence of exogenous LDL or whole serum in the normal prostate cells, but not in the prostate cancer cells. Addition of exogenous cholesterol down-regulated both LDLR and a potent regulator of the ldlr promoter, sterol regulatory element binding protein 2 (SREBP2), in normal cells but not in cancer cells. PGE2 synthesis in prostate cancer cells was significantly increased in response to LDL. Our study suggests that over-production of LDLR is an important mechanism in cancer cells for obtaining more essential fatty acids through LDLR endocytosis, allowing increased synthesis of prostaglandins, which subsequently stimulate cell growth. The data also suggest that the sterol regulatory element and SREBP2 play a role in the loss of sterol feedback regulation in cancer cells.

CCAAT-Enhancer-Binding Proteins↗

PubMed2003

Regulation of apoptosis by endoplasmic reticulum pathways.

Apoptotic programmed cell death pathways are activated by a diverse array of cell extrinsic and intrinsic signals, most of which are ultimately coupled to the activation of effector caspases. In many instances, this involves an obligate propagation through mitochondria, causing egress of critical proapoptotic regulators to the cytosol. Central to the regulation of the mitochondrial checkpoint is a complex three-way interplay between members of the BCL-2 family, which are comprised of an antiapoptotic subgroup including BCL-2 itself, and the proapoptotic BAX,BAK and BH3-domain-only subgroups. Constituents of all three of these BCL-2 classes, however, also converge on the endoplasmic reticulum (ER), an organelle whose critical contributions to apoptosis is only now becoming apparent. In addition to propagating death-inducing stress signals itself, the ER also contributes in a fundamental way to Fas-mediated apoptosis and to p53-dependent pathways resulting from DNA damage and oncogene expression. Mobilization of ER calcium stores can initiate the activation of cytoplasmic death pathways as well as sensitize mitochondria to direct proapoptotic stimuli. Additionally, the existence of BCL-2-regulated initiator procaspase activation complexes at the ER membrane has also been described. Here, we review the potential underlying mechanisms involved in these events and discuss pathways for ER-mitochondrial crosstalk pertinent to a number of cell death stimuli.

Amyloid beta-Protein Precursor↗

PubMed2000

Refinement of an ovarian cancer tumour suppressor gene locus on chromosome arm 22q and mutation analysis of CYP2D6, SREBP2 and NAGA.

Loss of heterozygosity on chromosome 22q was detected in 53% of 123 ovarian carcinomas, suggesting the presence of at least one tumour suppressor gene. We have refined the location of one possible tumour suppressor gene to the region between the microsatellite markers D22S299 and CYP2D. Located within this region are the genes SREBP2 (sterol regulatory element binding protein 2) and NAGA (N-acetyl-alpha-D-galactosaminidase). Investigation of the coding exons of these genes by single stranded conformational polymorphism/heteroduplex analysis failed to identify any somatic genetic alterations in 57 ovarian tumours which exhibited LOH on 22q13. The CYP2D gene locus straddles the distal boundary of the candidate region. Germline variants of the active CYP2D6 gene with differing abilities to metabolise specific substrates have been implicated in the development of various cancers. Comparison of the frequency of the two common germline mutations among 258 ovarian tumours and 231 non-cancer controls did not reveal any significant differences between the two groups. This suggests that the known polymorphic variants of CYP2D6 are not involved in ovarian cancer predisposition. We also conclude that neither NAGA nor SREBP2 are likely to be mutated in ovarian carcinomas.

Chromosome Mapping↗