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236 results on '"Bergo, Martin O."'

1. Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health

Author

Lecoutre, Simon, Maqdasy, Salwan, Rizo-Roca, David, Renzi, Gianluca, Vlassakev, Ivan, Alaeddine, Lynn M., Higos, Romane, Jalkanen, Jutta, Zhong, Jiawei, Zareifi, Danae S., Frendo-Cumbo, Scott, Massier, Lucas, Hodek, Ondrej, Juvany, Marta, Moritz, Thomas, de Castro Barbosa, Thais, Omar-Hmeadi, Muhmmad, López-Yus, Marta, Merabtene, Fatiha, Abatan, Jimon Boniface, Marcelin, Geneviève, El Hachem, Elie-Julien, Rouault, Christine, Bergo, Martin O., Petrus, Paul, Zierath, Juleen R., Clément, Karine, Krook, Anna, Mejhert, Niklas, and Rydén, Mikael

Published
2024
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4. Antioxidants stimulate BACHI-dependent tumor angiogenesis

Author

Wang, Ting, Dong, Yongqiang, Huang, Zhiqiang, Zhang, Guoqing, Zhao, Ying, Yao, Haidong, Hu, Jianjiang, Tuksammel, Elin, Cai, Huan, Liang, Ning, Xu, Xiufeng, Yang, Xijie, Schmidt, Sarah, Qiao, Xi, Schlisio, Susanne, Stromblad, Staffan, Qian, Hong, Jiang, Changtao, Treuter, Eckardt, and Bergo, Martin O.

Subjects
Thermo Fisher Scientific Inc., Scientific equipment and supplies industry -- Genetic aspects, Acetylcysteine, Genes -- Genetic aspects, Antioxidants, Cancer -- Genetic aspects -- Development and progression, Lung cancer -- Development and progression -- Genetic aspects, Genetic transcription -- Genetic aspects, DNA binding proteins -- Genetic aspects, Health care industry
Abstract

Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia- inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1-overexpressing cells and decreased in SACH7-knockout cells in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HfF7A-knockout and WT cells. BACH1 was found to be a transcriptional target of HIF1[alpha], but BACH1's ability to stimulate angiogenesis gene expression was HIF1[alpha] independent. Antioxidants increased tumor vascularity in vivo in a BACH1- dependent fashion, and overexpressing BACH1 rendered tumors sensitive to antiangiogenesis therapy. BACH1 expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor., Introduction Lung tumor growth and metastasis requires angiogenesis--the formation of new blood vessels (1, 2). Angiogenesis is typically triggered by hypoxia, which stabilizes hypoxia-inducible transcription factors (HIFs) including HIF1[alpha] and [...]

Published
2023
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9. Glutamine Links Obesity to Inflammation in Human White Adipose Tissue

Author

Petrus, Paul, Lecoutre, Simon, Dollet, Lucile, Wiel, Clotilde, Sulen, André, Gao, Hui, Tavira, Beatriz, Laurencikiene, Jurga, Rooyackers, Olav, Checa, Antonio, Douagi, Iyadh, Wheelock, Craig E., Arner, Peter, McCarthy, Mark, Bergo, Martin O., Edgar, Laurienne, Choudhury, Robin P., Aouadi, Myriam, Krook, Anna, and Rydén, Mikael

Published
2020
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15. Caution! Analyze transcripts from conditional knockout alleles

Author

Yang, Shao H., Bergo, Martin O., Farber, Emily, Qiao, Xin, Fong, Loren G., and Young, Stephen G.

Subjects
Biomedicine, Human Genetics, Plant Sciences, Animal Genetics and Genomics, Plant Genetics & Genomics, Molecular Medicine, Protein prenylation, Farnesylation, Prelamin A, HDJ-2, Knockout mice
Abstract

A common strategy for conditional knockout alleles is to “flox” (flank with loxP sites) a 5′ exon within the target gene. Typically, the floxed exon does not contain a unit number of codons so that the Cre-mediated recombination event yields a frameshift and a null allele. Documenting recombination within the genomic DNA is often regarded as sufficient proof of a frameshift, and the analysis of transcripts is neglected. We evaluated a previously reported conditional knockout allele for the β-subunit of protein farnesyltransferase. The recombination event in that allele—the excision of exon 3—was predicted to yield a frameshift. However, following the excision of exon 3, exon 4 was skipped by the mRNA splicing machinery, and the predominant transcript from the mutant allele lacked exon 3 and exon 4 sequences. The “∆exon 3–4 transcript” does not contain a frameshift but rather is predicted to encode a protein with a short in-frame deletion. This represents a significant concern when studying an enzyme, since an enzyme with partial function could lead to erroneous conclusions. With thousands of new conditional knockout alleles under construction within mouse mutagenesis consortiums, the protein farnesyltransferase allele holds an important lesson—to characterize knockout alleles at both the DNA and RNA levels.

Published
2009

24. Status of treatment strategies for Hutchinson-Gilford progeria syndrome with a focus on prelamin: A posttranslational modification

Author

Chen, Xue, Yao, Haidong, Andres, Vicente, Bergo, Martin O, Kashif, Muhammad, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Fundación La Marató TV3, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), and Progeria Research Foundation

Subjects
Progeria, Adolescent, Farnesyltranstransferase, Humans, Nuclear Proteins, Lamin Type A, Protein Processing, Post-Translational
Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular level, HGPS is caused by a de novo heterozygous mutation in LMNA, the gene encoding A-type lamins (mainly lamin A and C) and nuclear proteins, which have important cellular functions related to structure of the nuclear envelope. The LMNA mutation leads to the synthesis of a truncated prelamin A protein (called progerin), which cannot undergo normal processing to mature lamin A. In normal cells, prelamin A processing involves four posttranslational processing steps catalysed by four different enzymes. In HGPS cells, progerin accumulates as a farnesylated and methylated intermediate in the nuclear envelope where it is toxic and causes nuclear shape abnormalities and senescence. Numerous efforts have been made to target and reduce the toxicity of progerin, eliminate its synthesis and enhance its degradation, but as of today, only the use of farnesyltransferase inhibitors is approved for clinical use in HGPS patients. Here, we review the main current strategies that are being evaluated for treating HGPS, and we focus on efforts to target the posttranslational processing of progerin. Medicinska Forskningsrådet; Spanish Ministerio de Ciencia e Innovacion/ Agencia Estatal de Investigacion (AEI), Grant/Award Number: PID2019-108489RB-I00; Asociación Progeria Alexandra Peraut; Fundació la Marató TV3; European Regional Development Fund, Grant/Award Number: 202033; Swedish Medical Research Council; Progeria Research Foundation, Grant/Award Number: PRF 2019-77. Sí

Published
2022

33. Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

Author

Khan, Omar M., Ibrahim, Mohamed X., Jonsson, Ing-Marie, Karlsson, Christin, Liu, Meng, Sjogren, Anna-Karin M., Olofsson, Frida J., Brisslert, Mikael, Andersson, Sofia, Ohlsson, Claes, Hulten, Lillemor Mattsson, Bokarewa, Maria, and Bergo, Martin O.

Subjects
Rheumatoid factor -- Physiological aspects, Transferases -- Physiological aspects, Macrophages -- Physiological aspects, Rheumatoid arthritis -- Risk factors, Health care industry
Abstract

RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis., Introduction Small GTPases of RHO family proteins such as RAC1, RHOA, and CDC42 regulate the actin cytoskeleton during cell migration and phagocytosis and participate in intracellular signaling pathways (1, 2). [...]

Published
2011
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35. Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

Author

Gal, Kristell Le, Wiel, Clotilde, Ibrahim, Mohamed X., Henricsson, Marcus, Sayin, Volkan I., and Bergo, Martin O.

Subjects
lung cancer, lcsh:Therapeutics. Pharmacology, lcsh:RM1-950, mitochondria-targeted antioxidants, melanoma, mouse models, Article
Abstract

Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases, and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells, whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.

Published
2021

36. GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer

Author

Sjogren, Anna-Karin M., Andersson, Karin M.E., Liu, Meng, Cutts, Briony A., Karlsson, Christin, Wahlstrom, Annika M., Dalin, Martin, Weinbaum, Carolyn, Casey, Patrick J., Tarkowski, Andrej, Swolin, Birgitta, Young, Stephen G., and Bergo, Martin O.

Subjects
Lung cancer -- Research, Lung cancer -- Care and treatment, Lung cancer -- Analysis
Abstract

Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested [...]

Published
2007

38. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation

Author

Yang, Shao H., Meta, Margarita, Qiao, Xin, Frost, David, Bauch, Joy, Coffinier, Catherine, Majumdar, Sharmila, Bergo, Martin O., Young, Stephen G., and Fong, Loren G.

Subjects
Progeria -- Research, Phenotype -- Research
Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus. Progerin is targeted to the nuclear envelope [...]

Published
2006

40. Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice

Author

Fong, Loren G., Ng, Jennifer K., Meta, Margarita, Cote, Nathan, Yang, Shao H., Stewart, Colin L. Sullivan, Terry, Burghardt, Andrew, Majumdar, Sharmila, Reue, Karen, Bergo, Martin O., and Young, Stephen G.

Subjects
Progeria -- Research, Science and technology
Abstract

Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste[24.sup.-/-]) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste[24.sup.-/-] mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste[24.sup.-/-] mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste[24.sup.-/-] mice with half-normal levels of prelamin A (Zmpste[24.sup.-/-] mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, we bred and analyzed Zmpste[24.sup.-/-]Lmn[a.sup,+/-] mice. As expected, prelamin A levels in Zmpste[24.sup.-/-]Lmn[a.sup.+/-] cells were significantly reduced. Zmpste[24.sup.-/-]Lmn[a.sup.+/-] mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste[24.sup.-/-]Lmn[a.sup.+/-] ceils than in Zmpste[24.sup.-/-] cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease. Hutchinson-Gilford progeria syndrome | prelamin A

Published
2004

47. Prelamin A and lamin A appear to be dispensable in the nuclear lamina

Author

Fong, Loren G., Ng, Jennifer K., Lammerding, Jan, Vickers, Timothy A., Meta, Margarita, Coté, Nathan, Gavino, Bryant, Qiao, Xin, Chang, Sandy Y., Young, Stephanie R., Yang, Shao H., Stewart, Colin L., Lee, Richard T., Bennett, C. Frank, Bergo, Martin O., and Young, Stephen G.

Published
2006

50. Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice

Author

Nallapalli Rajesh K, Ibrahim Mohamed X, Zhou Alex X, Bandaru Sashidar, Sunkara Sai Naresh, Redfors Björn, Pazooki David, Zhang Yin, Borén Jan, Cao Yihai, Bergo Martin O, and Akyürek Levent M

Subjects
Cancer, Angiogenesis, Cytoskeleton, Migration, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. Methods First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. Results Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. Conclusions We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.

Published
2012
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