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1.
Cell Death Dis ; 4: e547, 2013 Mar 21.
Article in English | MEDLINE | ID: mdl-23519116

ABSTRACT

Previous studies proposed that myosin-Va regulates apoptosis by sequestering pro-apoptotic Bmf to the actin cytoskeleton through dynein light chain-2 (DLC2). Adhesion loss or other cytoskeletal perturbations would unleash Bmf, allowing it to bind and inhibit pro-survival Bcl2 proteins. Here, we demonstrated that overexpression of a myosin-Va medial tail fragment (MVaf) harboring the binding site for DLC2 dramatically decreased melanoma cell viability. Morphological and molecular changes, including surface blebbing, mitochondrial outer membrane permeabilization, cytochrome-c and Smac release, as well as caspase-9/-3 activation and DNA fragmentation indicated that melanoma cells died of apoptosis. Immobilized MVaf interacted directly with DLCs, but complexed MVaf/DLCs did not interact with Bmf. Overexpression of DLC2 attenuated MVaf-induced apoptosis. Thus, we suggest that, MVaf induces apoptosis by sequestering DLC2 and DLC1, thereby unleashing the pair of sensitizer and activator BH3-only proteins Bmf and Bim. Murine embryonic fibroblasts (MEFs) lacking Bim and Bmf or Bax and Bak were less sensitive to apoptosis caused by MVaf expression than wild-type MEFs, strengthening the putative role of the intrinsic apoptotic pathway in this response. Finally, MVaf expression attenuated B16-F10 solid tumor growth in mice, suggesting that this peptide may be useful as an apoptosis-inducing tool for basic and translational studies.


Subject(s)
Cytoplasmic Dyneins/genetics , Gene Expression Regulation, Neoplastic/drug effects , Melanoma/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Peptide Fragments/genetics , Skin Neoplasms/genetics , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/deficiency , Apoptosis Regulatory Proteins/genetics , Bcl-2-Like Protein 11 , Cell Line, Tumor , Cytoplasmic Dyneins/metabolism , DNA Fragmentation/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Melanoma/metabolism , Melanoma/pathology , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Knockout , Myosin Heavy Chains/metabolism , Myosin Type V/metabolism , Neoplasm Transplantation , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Protein Binding , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , Signal Transduction/drug effects , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , bcl-2 Homologous Antagonist-Killer Protein/deficiency , bcl-2 Homologous Antagonist-Killer Protein/genetics
2.
J Hum Hypertens ; 27(1): 31-7, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22189703

ABSTRACT

We examined whether vascular endothelial growth factor (VEGF) polymorphisms (C-2578A, G-1154A and G-634C) are associated with hypertension, response to antihypertensive therapy and nitric oxide (NO) formation. Substudy 1 compared the distribution of VEGF genotypes and haplotypes in 178 patients with arterial hypertension (100 whites and 78 blacks) and 186 healthy controls (115 whites and 71 blacks). Substudy 2 compared the distribution of VEGF markers in 82 patients with controlled hypertension, 89 patients with resistant hypertension and 101 normotensive (NT) patients. In substudy 3, plasma nitrite/nitrate (NOx) levels were determined (chemiluminescence assay) in 64 NT subjects and 48 hypertensive (HTN) subjects, and the distribution of VEGF markers was compared in subjects having low NOx with subjects having high NOx. Although the substudy 1 showed no differences in genotypes or allele distributions for the three VEGF polymorphisms between NT and HTN subjects, the 'C-A-G' haplotype was more common in white NT subjects than in the white HTN subjects, and the 'C-A-C' haplotype was more frequent in black and white HTN subjects than in black and white NT subjects. The substudy 2 showed similar results, with no differences between responsive and resistant HTN subjects. The substudy 3 showed that the 'C-A-G' haplotype, which had a protective effect against hypertension, was significantly more common in subjects with higher NOx concentrations than in subjects with lower NOx concentrations. VEGF haplotypes are associated with hypertension, and the haplotype associated with normotension was more common in subjects with increased NO formation, possibly offering a mechanistic clue for our findings.


Subject(s)
Genetic Predisposition to Disease , Haplotypes , Hypertension/genetics , Vascular Endothelial Growth Factor A/genetics , Adult , Female , Genotype , Humans , Hypertension/metabolism , Male , Middle Aged , Nitric Oxide/biosynthesis
3.
Int J Obes (Lond) ; 36(1): 69-75, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21844877

ABSTRACT

OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) is involved in the atherosclerotic process and functional polymorphisms in the MMP-9 gene affect MMP-9 expression/activity, and are associated with cardiovascular diseases. However, no study has tested the hypothesis that functional MMP-9 polymorphisms could affect MMP-9 levels in obese children. We investigated whether three MMP-9 gene polymorphisms (C-1562T (rs3918242), 90(CA)((14-24)) (rs2234681) and Q279R (rs17576)), or haplotypes, affect MMP-9 levels in obese children. METHODS: We studied 175 healthy control children and 127 obese children. Plasma MMP-9, tissue inhibitor of MMPs (TIMP)-1 and adiponectin concentrations were measured using enzyme-linked immunosorbent assay. RESULTS: We found similar MMP-9 genotypes, allelic and haplotypes distributions in the two study groups (P>0.05). However, we found lower plasma MMP-9 concentrations in obese subjects carrying the CC or the QQ genotypes for the C-1562T and the Q279R polymorphisms, respectively, in obese children compared with children with the other genotypes, or with non-obese children with the same genotypes (all P<0.05). Moreover, we found lower MMP-9 levels and lower MMP-9/TIMP-1 ratios (which reflect net MMP-9 activity) in obese children carrying the H2 haplotype (which combines the C, H and Q alleles for the three polymorphisms, respectively) when compared with obese children carrying the other haplotypes, or with non-obese children carrying the same haplotype (P<0.05). CONCLUSIONS: Our findings show that MMP-9 genotypes and haplotypes affect MMP-9 levels in obese children and adolescents, and suggest that genetic factors may modify relevant pathogenetic mechanisms involved in the development of cardiovascular complications associated with obesity in childhood.


Subject(s)
Cardiovascular Diseases/genetics , Matrix Metalloproteinase 9/genetics , Obesity/genetics , Polymorphism, Single Nucleotide , Adiponectin/blood , Cardiovascular Diseases/blood , Cardiovascular Diseases/epidemiology , Child , Enzyme-Linked Immunosorbent Assay , Female , Haplotypes , Humans , Male , Matrix Metalloproteinase 9/blood , Obesity/blood , Obesity/epidemiology , Tissue Inhibitor of Metalloproteinase-1/blood
4.
Pharmacogenomics J ; 10(1): 40-5, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19704415

ABSTRACT

Variations of the endothelial nitric oxide synthase (eNOS) gene have been associated with hypertensive disorders of pregnancy. We examined whether eNOS polymorphisms affect the therapeutic responses of women with gestational hypertension (GH) or preeclampsia (PE). We studied 304 hypertensive pregnant women (152 GH and 152 PE), who were stratified according to clinical and laboratorial parameters of therapeutic responsiveness. We compared the frequencies of three eNOS genetic polymorphisms (T-786C, Glu298Asp and b/a intron 4) in responsive and nonresponsive PE and GH patients. We found no significant differences in genotype or allele distributions when responsive and nonresponsive groups were compared (both PE or GH; all P>0.05). However, the eNOS haplotype distribution differed in PE (but not in GH)-responsive and -nonresponsive groups (P=0.0003). The 'C-Glu-a' and 'T-Asp-a' hapotypes were associated with responsiveness and nonresponsiveness to therapy, respectively (both P<0.001), thus suggesting that eNOS haplotypes affect the responsiveness to antihypertensive therapy in PE.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension, Pregnancy-Induced/genetics , Nitric Oxide Synthase Type III/genetics , Pre-Eclampsia/genetics , Adult , Female , Gene Frequency , Genotype , Haplotypes , Humans , Hypertension, Pregnancy-Induced/drug therapy , Polymorphism, Genetic , Pre-Eclampsia/drug therapy , Pregnancy
5.
Braz J Med Biol Res ; 41(10): 839-48, 2008 Oct.
Article in English | MEDLINE | ID: mdl-19030707

ABSTRACT

Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1, Elejalde), RAB27A (GS2) or MLPH (GS3) genes. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and hemophagocytic syndrome. We report here the diagnosis of GS2 in 3-year-old twin siblings, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death. Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. A homozygous nonsense mutation, C-T transition (c.550C>T), in the coding region of the RAB27A gene, which leads to a premature stop codon and prediction of a truncated protein (R184X), was found. In patient mononuclear cells, RAB27A mRNA levels were the same as in cells from the parents, but no protein was detected. In addition to the case report, we also present an updated summary on the exon/intron organization of the human RAB27A gene, a literature review of GS2 cases, and a complete list of the human mutations currently reported in this gene. Finally, we propose a flow chart to guide the early diagnosis of the GS subtypes and Chédiak-Higashi syndrome.


Subject(s)
Diseases in Twins/genetics , Hair Color/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Mutation/genetics , Pigmentation Disorders/genetics , rab GTP-Binding Proteins/genetics , Child, Preschool , Diseases in Twins/diagnosis , Fatal Outcome , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , Pigmentation Disorders/diagnosis , Syndrome , rab27 GTP-Binding Proteins
6.
Braz. j. med. biol. res ; 41(10): 839-848, Oct. 2008. ilus, tab
Article in English | LILACS | ID: lil-496814

ABSTRACT

Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1, Elejalde), RAB27A (GS2) or MLPH (GS3) genes. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and hemophagocytic syndrome. We report here the diagnosis of GS2 in 3-year-old twin siblings, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death. Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. A homozygous nonsense mutation, C-T transition (c.550C>T), in the coding region of the RAB27A gene, which leads to a premature stop codon and prediction of a truncated protein (R184X), was found. In patient mononuclear cells, RAB27A mRNA levels were the same as in cells from the parents, but no protein was detected. In addition to the case report, we also present an updated summary on the exon/intron organization of the human RAB27A gene, a literature review of GS2 cases, and a complete list of the human mutations currently reported in this gene. Finally, we propose a flow chart to guide the early diagnosis of the GS subtypes and Chédiak-Higashi syndrome.


Subject(s)
Child, Preschool , Humans , Male , Diseases in Twins/genetics , Hair Color/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Mutation/genetics , Pigmentation Disorders/genetics , rab GTP-Binding Proteins/genetics , Diseases in Twins/diagnosis , Fatal Outcome , Lymphohistiocytosis, Hemophagocytic/diagnosis , Pigmentation Disorders/diagnosis , Syndrome
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