Oncogenic gsp proteins appear to stimulate the transformation of pituitary somatotrophs by inducing the constitutive activation of adenyl cyclase. Previous work implicating the cAMP-responsive transcription factor CREB as a biochemical intermediate in the proliferative response to cAMP led us to examine whether CREB activity was correspondingly elevated in human somatotroph adenomas. In a series of 15 human GH-secreting tumors, we found that each of these contained elevated levels of Ser133-phosphorylated and, hence, activated CREB compared with nonfunctioning pituitary tumors. Four of the GH-secreting adenomas contained an oncogenic gsp gene by polymerase chain reaction analysis, and two additional adenomas expressed wild-type G alpha s protein at 5- to 10-fold higher levels than nonfunctioning pituitary tumors. As both oncogenic gsp and overexpressed G alpha s proteins can induce Ser133 phosphorylation and cAMP-responsive gene expression in transfected GC somatotroph cells, our studies indicate that these proteins may promote somatotroph transformation in part by inducing the transcription of specific CREB-dependent target genes.