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The interaction between Wnt canonical pathway with PRKAR1A and PDE8B in adrenocortical tumor development and/or progression by using a transgenic mouse model

Grant number: 13/05337-3
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): September 01, 2013
Effective date (End): August 31, 2014
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Sonir Roberto Rauber Antonini
Grantee:Letícia Ferro Leal
Supervisor: Constantine A. Stratakis
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: National Institutes of Health, Bethesda (NIH), United States  
Associated to the scholarship:11/10512-3 - Analysis of Wnt/{beta}-catenin pathway in childhood adrencortical tumors, BP.DR


Background and Introduction: Adrenal tumorigenesis appears to result of a combination of two or more genetic hits but little is known about this complex crosstalk. Beta-catenin mutations and other WNT pathway abnormalities are frequently found in adrenal tumors. Primary pigmented nodular adrenocortical disease (PPNAD), a rare form of bilateral micronodular adrenocortical hyperplasia, has been associated with inactivating mutations in PRKAR1A gene. Prkar1a haploinsufficiency alone does not appear to be sufficient to promote tumor formation but predisposes to tumor formation in a spectrum of endocrine and non-endocrine tissues that are cAMP-responsive. A transcriptome profiling of tumors produced by mouse models of Prkar1a haploinsufficiency identified Wnt pathway as the main pathway activated by abnormal cAMP signaling. Mutations in PDE8B, coding for phosphodiesterases (PDEs) have been found in patients with hyperplasias and adrenal tumors, however, remains unclear if these alterations could be causal for the disease. Together, these data suggest the importance of PRKAR1A, WNT and PDE8B in adrenal tumorigenesis. However, it is currently unknown whether abnormalities in these pathways synergize to initiate and/or increase adrenal tumor progression.Aim: To evaluate the possible induction of the WNT canonical pathway by Prkar1a or PDE8B or both in adrenocortical tumor development and/or progression.Methods: A strain of double mutant mice will be obtained by crossing beta-catenin mutant mice (DCat mouse) with the Pde8b knock-out (Pde8b-/-); data will be compared with the Prkar1a-loxP/loxP/Cre+ AdKO mouse that is being created by Dr. Stratakis'collaborators. The genotype will be confirmed by PCR and sequencing, Adrenal and other tumors development will be longitudinally analyzed. Plasma ACTH and corticosterone levels will be evaluated by RIA. PKA activity and the expression levels of the main genes enrolled in Wnt, Prkar1a and cAMP/Pde pathways will be analyzed by qPCR, Western blotting and Immunostaining in Adrenal tissues.Perspectives: This work might contribute to explain some mechanisms involved in tumor development and progression and whether Pde8b impairment and/or the Prkar1a haploinsufficiency may increase ²-catenin-driven adrenal tumorigenesis. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LEAL, LETICIA FERRO; SZAREK, EVA; BERTHON, ANNABEL; NESTEROVA, MARIA; FAUCZ, FABIO R.; LONDON, EDRA; MERCIER, CHRISTOPHER; ABU-ASAB, MONES; STAROST, MATTHEW F.; DYE, LOUIS; et al. Pde8b haploinsufficiency in mice is associated with modest adrenal defects, impaired steroidogenesis, and male infertility, unaltered by concurrent PKA or Wnt activation. Molecular and Cellular Endocrinology, v. 522, . (13/05337-3)

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