The pituitary adenylate cyclase-activating polypeptide (PACAP)/ glucagon superfamily includes nine hormones in humans that are related by structure, distribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors). The nine hormones include glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose-dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), peptide histidine-methionine (PHM), PACAP, secretin, and vasoactive intestinal polypeptide (VIP). The origin of the ancestral superfamily members is at least as old as the invertebrates; the most ancient and tightly conserved members are PACAP and glucagon. Evidence to date suggests the superfamily began with a gene or exon duplication and then continued to diverge with some gene duplications in vertebrates. The function of PACAP is considered in detail because it is newly (1989) discovered; it is tightly conserved (96% over 700 million years); and it is probably the ancestral molecule. The diverse functions of PACAP include regulation of proliferation, differentiation, and apoptosis in some cell populations. In addition, PACAP regulates metabolism and the cardiovascular, endocrine, and immune systems, although the physiological event(s) that coordinates PACAP responses remains to be identified.

Apoptosis and inhibition of mitosis are primary mechanisms mediating androgen ablation therapy-induced regression of prostate cancer (PCa). However, PCa readily becomes androgen independent, leading to fatal disease. Up-regulated growth and survival signaling is implicated in development of resistance to androgen ablation therapy. We are testing the hypothesis that insulin-like growth factor (IGF) responsiveness is required for androgen-independent (AI) progression. Using the LNCaP human PCa progression model, we have determined that IGF-I-mediated protection from apoptotic stress and enhanced mitotic activity is androgen dependent in LNCaP cells but is androgen independent in lineage-derived C4-2 cells. Both cell lines exhibit androgen-responsive patterns of IGF-I receptor (IGF-IR) expression, activation, and signaling to insulin receptor substrate-2 and AKT. However, C4-2 cells express higher levels of IGF-IR mRNA and protein and exhibit enhanced IGF-I-mediated phosphorylation and downstream signaling under androgen-deprived conditions. In comparisons of naïve and AI metastatic human PCa specimens, we have confirmed that IGF-IR levels are elevated in advanced disease. Together with our LNCaP/C4-2 AI progression model data, these results indicate that increased IGF-IR expression is associated with AI antiapoptotic and promitotic IGF signaling in PCa disease progression.

Three species of fish have become important in the study of reproduction and development. Rockfish are a model for developmental studies of live-bearing perch-like fish, whereas medaka and zebrafish are models for developmental and genetic studies. The forms of GnRH are identified in the brains of each of these fish and in the pituitary of the rockfish to investigate the role of GnRH in reproduction. Here, we report that grass rockfish (Sebastes rastrelliger) have three forms of GnRH in brain extracts as determined by HPLC elution position and RIA. These forms are identified as sea bream GnRH, chicken GnRH-II and salmon GnRH. In contrast, only two forms of GnRH were detected in brain extracts of medaka (Oryzias latipes) and zebrafish (Brachydanio rerio): salmon GnRH and chicken GnRH-II. Rockfish is distinct from medaka and zebrafish in that the most abundant form of GnRH in the rockfish pituitary is sea bream GnRH, whereas this form is absent in the other two fishes. The identification of sea bream GnRH in the rockfish brain and pituitary extracts indicates that the phylogenetic emergence of sea bream GnRH is earlier than the order Perciformes.

Growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP) are structurally and functionally related members of the glucagon superfamily, a group of hormones important in development, growth, and metabolism. Our objectives were to determine the developmental expression pattern of the ghrh-pacap1 gene using the zebrafish model. The temporal and spatial expression pattern of the ghrh-pacap1 gene was examined by RT-PCR and in situ hybridization. In zebrafish, the ghrh-pacap1 mRNA transcript was expressed throughout development beginning at the transition between the blastula and gastrula periods. During midgastrulation, alternative splicing resulted in the generation of a novel transcript lacking the cryptic peptide. During the segmentation period, expression was localized to the neural tube, developing eye, and neural crest; strong expression was found in the developing cerebellum. Later in development, expression was localized in the hatching gland and developing pharyngeal arches. The temporal and spatial expression pattern of the ghrh-pacap1 transcript suggests that these hormones may modulate patterning during development.