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Abstract:

Heme oxygenase-1 (HO-1), an inducible enzyme that metabolizes the heme group, is highly expressed in human Kaposi sarcoma lesions. Its expression is up-regulated by the G protein-coupled receptor from the Kaposi sarcoma-associated herpes virus (vGPCR). Although recent evidence shows that HO-1 contributes to vGPCR-induced tumorigenesis and vascular endothelial growth factor (VEGF) expression, the molecular steps that link vGPCR to HO-1 remain unknown. Here we show that vGPCR induces HO-1 expression and transformation through the Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA. Targeted small hairpin RNA knockdown expression of Gα12, Gα13, or RhoA and inhibition of RhoA activity impair vGPCR-induced transformation and ho-1 promoter activity. Knockdown expression of RhoA also reduces vGPCR-induced VEFG-A secretion and blocks tumor growth in a murine allograft tumor model. NIH-3T3 cells expressing constitutively activated Gα13 or RhoA implanted in nude mice develop tumors displaying spindle-shaped cells that express HO-1 and VEGF-A, similarly to vGPCR-derived tumors. RhoAQL-induced tumor growth is reduced 80% by small hairpin RNA-mediated knockdown expression of HO-1 in the implanted cells. Likewise, inhibition of HO-1 activity by chronic administration of the HO-1 inhibitor tin protoporphyrin IX to mice reduces RhoAQL-induced tumor growth by 70%. Our study shows that vGPCR induces HO-1 expression through the Gα12/13/RhoA axes and shows for the first time a potential role for HO-1 as a therapeutic target in tumors where RhoA has oncogenic activity.

Registro:

Documento: Artículo
Título:The Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis
Autor:Martín, M.J.; Tanos, T.; García, A.B.; Martin, D.; Gutkind, J.S.; Coso, O.A.; Marinissen, M.J.
Filiación:Instituto de Investigaciones Biomédicas A. Sols, Departamento de Bioquímica, Universidad Autónoma de Madrid, Madrid 28029, Spain
Departamento de Fisiología Y Biología Molecular, Facultad de Ciencias Exactas Y Naturales, IFYBYNE-CONICET, 1428 Buenos Aires, Argentina
Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, MD 20892, United States
Instituto de Investigaciones Biomédicas A. Sols, Dept. de Bioquimica, Universidad Autonoma de Madrid, Arzobispo Morcillo 4, Madrid 28029, Spain
Palabras clave:Kaposi sarcoma lesions; Oncogenic activity; Tumor growth; Tumorigenesis; Cells; Enzyme activity; Gene expression; RNA; Tumors; Proteins; G protein coupled receptor; guanine nucleotide binding protein; guanine nucleotide binding protein alpha12; guanine nucleotide binding protein alpha13; guanosine triphosphatase; heme oxygenase 1; heme oxygenase inhibitor; heterotrimeric guanine nucleotide binding protein; protoporphyrin; RhoA guanine nucleotide binding protein; short hairpin RNA; unclassified drug; vasculotropin A; chemokine receptor; G protein coupled receptor, Human herpesvirus 8; G protein-coupled receptor, Human herpesvirus 8; guanine nucleotide binding protein alpha subunit; heme oxygenase 1; photosensitizing agent; protoporphyrin; RhoA guanine nucleotide binding protein; RHOA protein, human; VEGFA protein, human; allograft; animal cell; animal experiment; animal model; article; carcinogenesis; cell proliferation; cell strain 3T3; cell survival; controlled study; enzyme activity; human; human cell; Human herpesvirus 8; Kaposi sarcoma; mouse; nonhuman; nude mouse; priority journal; protein expression; protein function; tumor growth; animal; drug antagonism; drug effect; drug screening; gene expression regulation; genetics; Human herpesvirus 8; metabolism; promoter region; secretion; virus cell transformation; Herpesviridae; Murinae; Mus; Mus musculus; Animals; Cell Transformation, Viral; Gene Expression Regulation, Neoplastic; GTP-Binding Protein alpha Subunits, Gq-G11; Heme Oxygenase-1; Herpesvirus 8, Human; Humans; Mice; Mice, Nude; NIH 3T3 Cells; Photosensitizing Agents; Promoter Regions (Genetics); Protoporphyrins; Receptors, Chemokine; rhoA GTP-Binding Protein; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays
Año:2007
Volumen:282
Número:47
Página de inicio:34510
Página de fin:34524
DOI: http://dx.doi.org/10.1074/jbc.M703043200
Título revista:Journal of Biological Chemistry
Título revista abreviado:J. Biol. Chem.
ISSN:00219258
CODEN:JBCHA
CAS:guanosine triphosphatase, 9059-32-9; protoporphyrin, 553-12-8; vasculotropin A, 489395-96-2; G protein-coupled receptor, Human herpesvirus 8; GTP-Binding Protein alpha Subunits, Gq-G11, 3.6.1.46; Heme Oxygenase-1, 1.14.99.3; Photosensitizing Agents; Protoporphyrins; RHOA protein, human, 124671-05-2; Receptors, Chemokine; VEGFA protein, human; Vascular Endothelial Growth Factor A; protoporphyrin IX, 553-12-8; rhoA GTP-Binding Protein, 3.6.5.2
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_00219258_v282_n47_p34510_Martin.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v282_n47_p34510_Martin

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Citas:

---------- APA ----------
Martín, M.J., Tanos, T., García, A.B., Martin, D., Gutkind, J.S., Coso, O.A. & Marinissen, M.J. (2007) . The Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis. Journal of Biological Chemistry, 282(47), 34510-34524.
http://dx.doi.org/10.1074/jbc.M703043200
---------- CHICAGO ----------
Martín, M.J., Tanos, T., García, A.B., Martin, D., Gutkind, J.S., Coso, O.A., et al. "The Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis" . Journal of Biological Chemistry 282, no. 47 (2007) : 34510-34524.
http://dx.doi.org/10.1074/jbc.M703043200
---------- MLA ----------
Martín, M.J., Tanos, T., García, A.B., Martin, D., Gutkind, J.S., Coso, O.A., et al. "The Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis" . Journal of Biological Chemistry, vol. 282, no. 47, 2007, pp. 34510-34524.
http://dx.doi.org/10.1074/jbc.M703043200
---------- VANCOUVER ----------
Martín, M.J., Tanos, T., García, A.B., Martin, D., Gutkind, J.S., Coso, O.A., et al. The Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis. J. Biol. Chem. 2007;282(47):34510-34524.
http://dx.doi.org/10.1074/jbc.M703043200