Assessment of cell cycle genes and ribosomal proteins in the molecular pathogenesis of pituitary adenomas

• Grant number: 12/02234-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): May 01, 2012
• Effective date (End): September 30, 2014
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Margaret de Castro
• Grantee: Clarissa Silva Martins
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Ribosomal Proteins (RPs) are involved in most cellular functions. Besides acting on protein synthesis, they also have extraribosomal functions. Recent data shows their ability to modulate gene expression, including regulation of cell cycle genes. Additionally, RPs have been recently related to human tumorigenesis. The interaction between cyclins and CDKs (cyclin dependent kinases) is a fundamental step in cell replication. CDKN1B/p27kip1 gene is a negative cell cycle regulator and prevents cyclin E and CDK2 association. This gene is also a target for the c-MYC oncogene pathway. RPS13 inhibits CDKN1B/p27kip1 expression in gastric carcinoma, suggesting a potential role for this protein in cancer development. CDKN1B/p27kip1 mRNA is not translated in Multiple Endocrine Neoplasia type 4 (MEN 4) tumors and is underexpressed in sporadic pituitary adenomas, indicating a post-transcriptional regulatory mechanism. There are no studies evaluating CDKN1B/p27kip1 and RPS13 expression in pituitary adenomas. In addition, DKC1 gene encodes dyskerin, a pseudouridine synthase, which modifies ribosomal RNA. Decrease in its activity impairs translation of mRNA containing Internal Ribosomal Entry Site (IRES) elements, including CDKN1B/p27kip1. In mice, the reduction of dyskerin activity resulted in impaired CDKN1B/p27kip1 translation and increased incidence of pituitary adenomas. In humans, a new DKC1 somatic mutation (DKC1S485G) was found in a pituitary adenoma. Therefore, we hypothesized whether ribosomal proteins, such as RPS13, might play a role in human pituitary tumorigenesis, mainly by modulating CDKN1B/p27kip1. In order to evaluate the interaction of ribosomal proteins and cell cycle regulator genes in the molecular pathogenesis of pituitary adenomas, the present study aims to search for mutations and hypermethylation of DCK1 gene in these tumors; to assess the c-MYC, DKC1, CDKN1B/p27kip1, CDK2 and RPS13 expression in non-secreting, and in GH- and ACTH- secreting pituitary adenomas as well as in pituitary tumor cell lineages, using gene expression (qPCR) and protein (Western blot) analysis; to evaluate the relationship between gene expression and clinical findings, such as tumor size, recurrence, and aggressiveness. (AU)

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)

MARTINS, C. S.; CAMARGO, R. C.; SAGGIORO, F. P.; NEDER, L.; MACHADO, H. R.; MOREIRA, A. C.; DE CASTRO, M.. P27/CDKN1B Translational Regulators in Pituitary Tumorigenesis. Hormone and Metabolic Research, v. 48, n. 12, p. 840-846, DEC 2016. (12/02234-6)

LUIS GUILHERME F. RODRIGUES; LEONARDO D. DE ARAUJO; SILVIA L. R. ROA; ANA C. BUENO; ERNANE T. UCHOA; JOSÉ ANTUNES-RODRIGUES; AYRTON C. MOREIRA; LUCILA L. K. ELIAS; MARGARET DE CASTRO; CLARISSA S. MARTINS. Restricted feeding modulates peripheral clocks and nutrient sensing pathways in rats. ARCHIVES OF ENDOCRINOLOGY METABOLISM, v. 65, n. 5, p. 549-561, 2021-09-29. (12/02234-6)