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Assessment of genes involved in controlling cell proliferation and apoptosis in the molecular pathogenesis of pituitary adenomas

Grant number: 12/00319-4
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2012
Effective date (End): May 31, 2015
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Margaret de Castro
Grantee:Renata Costa Camargo
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


The molecular pathogenesis of pituitary tumors remains uncharacterized. Mutations in proto-oncogenes and tumor suppressor genes have been rarely identified. Loss of checkpoint control of the cell cycle resulting in genomic instability, accumulation of DNA damage and uncontrolled cell proliferation has been associated with tumor progression. Cyclins and kinases are also involved in the cell cycle regulation. The kinases, when activated by cyclins, phosphorylate proteins, such as pRb, necessary for cell division. The p53 is another protein with an important role in the cellular response to DNA damage. p53 phosphorylation increases the transcription of several genes blocking the activation of CDKs and cell cycle progression from G1 to S phases and induces apoptosis. Recently, several studies have been show the role of ribosomal proteins in tumorigenesis and in the cell cycle regulation, since they are able to regulate gene transcription and translation. RPL11, RPL5, RPL23, RPL7 and RPS3 are able to binding to the MDM2 oncoprotein, increasing the p53 stability. Additionally, ribosomal protein RPL11 can regulate the stability of the c-myc mRNA and control the transcription of its target genes. These data suggest that genes involved in cell proliferation and apoptosis such as BTG2, MDM2, c-Myc, RB1, TP53, E2F, CDK4/6, regulated by ribosomal proteins RPL11 and RPS3 may be involved in the molecular pathogenesis of tumors. There are no studies evaluating this hypothesis in pituitary tumors. Thus, the aim of our study is to assess gene and protein expression of BTG2, MDM2, c-Myc, RB1, TP53, E2F, CDK4/6, RPS11 e RPS3 in cortitotrophinomas, somatotropinomas and non functioning pituitary adenoma. Moreover, to evaluate the expression of these genes and protein in tumoral lineages such as corticotrophic (AtT-20), somatotrophic (GH3) and non functioning (±T3-1). The role of over and/or underexpression genes will be confirmed by functional analysis.

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