G-PROTEINS AND HORMONAL SIGNALING IN HUMAN PITUITARY-TUMORS - GENETICMUTATIONS AND FUNCTIONAL ALTERATIONS

In the last few years, molecular studies on pituitary adenomas have yi elded several lines of evidence supporting a primary pituitary origin for these tumors. In fact, analyses of x-chromosomal inactivation show that the great majority of pituitary tumors are monoclonal in origin, suggesting that one or more mutations are responsible for the selecti ve expansion of a single cell clone. Mutations constitutively activati ng GTP-binding proteins have been identified in subsets of pituitary a denomas. Single amino acid substitutions replacing Arg 201 with either Cys, His, or Gln 227 with either Arg or Leu of the alpha-subunit of t he Gs gene were identified in one third of growth hormone (GH)-secreti ng adenomas. Both mutations stabilize alphas in its active conformatio n by inhibiting GTPase activity, thus mimicking the effect of specific extracellular growth factors, such as growth hormone releasing hormon e (GHRH). Since several lines of evidence suggest that cAMP is involve d in somatotrope replication, it has been proposed that the alphas gen e can be converted into an oncogene, designated gsp (for Gs protein). Recently, the ras oncogene has been identified in one prolactinoma cha racterized by unusual invasiveness. Although these data seem to negate a primary role for hypothalamic neurohormones in adenoma formation, i t is conceivable that the hormones may exert a role in the sequence of events leading to clonal expansion of a transformed cell. Moreover, a lterations in receptor and/or postreceptor events triggered by hypotha lamic neurohormones may result in amplification of stimulatory inputs and impairment of inhibitory ones.