Mitogenetic activity and transduction of the signal of the adrenocorticotropic hormone (ACTH)

• Grant number: 97/12755-1
• Support Opportunities: Research Projects - Thematic Grants
• Duration: April 01, 1998 - June 30, 2002
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Hugo Aguirre Armelin
• Grantee: Hugo Aguirre Armelin
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

This project focuses on the mitogenic action of the adrenocorticotropic hormone (ACTH). This is an important problem of celular and molecular endrocrinology of the adrenal cortex and, in addition, is heuristacally promising from the view point of studies on cell cycle control mechanisms. For decades ACTH is known for promoting growth of the adrenal cortex "in vivo". However, about 20 years ago, it was shown that ACTH blocks cell cycle and inhibits proliferation of adrenocortical cells isolated in culture. This last observation led to the belief that ACTH was an indirect mitogen "in vivo". But, in the last 4 years we obtained and consolidated results showing that ACTH displays a mitogenic activity of its own. Our results, with the Y-1 cell line of mouse adrenal cells, show that ACTH causes two antagonistic effects on the G0-G1-S transition of cell cycle: it stimulates G0-G1 (mitogenic effect) and inhibits G1-S (antimitogenic effect). Previous experimental protocols, from ours and other laboratories, systematically displayed the ACTH inhibitory effect, missing its stimulatory effect. The objectives of this project are to study the molecular mechanisms that can explain these antagonistic effects of ACTH. The cAMP/PKA vua has classically been recognised as the only signal tranduction route for all effects of ACTH. Presently, this statement is no longer valid. We reported that ACTH induces the genes of the fos and jun families by a process that involve regulatory routes other thatn the cAMP/PKA (Kimura & Armelin, 90; Kimura et all, 93a; 93b). More recently, our results indicate that the ACTH inhibition of G1-S transition is dependent on PKA, whereas the stimulation of G0-G1 transition is idependent of PKA (Armelin et all, 96; Lofti et al, 97). These data prompted us to raise the following hypotheses: a) ACTH-Rec initiate different signals that independently mediate the two antagonistic effects of ACTH on the G0-G1-S transition; b) ACTH-Rec initiate signals that lead to activation of the Ras/Raf/ERK cascade, normally activated by tyrosine kinase receptors. Furthermore; d) the induction of the fos and jun genes is necessary to stimulate the G0-G1 transition (mitogenic effect); e) the inhibition of c-Myc expression is part of the mechanism that block the G1-S transition (antimitogenic effect). A series of specific objectives and respective experimental protocols were designed to test these hypotheses. (AU)