A glycoprotein hormone expressed in corticotrophs exhibits unique binding properties on thyroid-stimulating hormone receptor.

Corticotroph-derived glycoprotein hormone (CGH), also referred to as thyrostimulin, is a noncovalent heterodimer of glycoprotein hormone alpha 2 (GPHA2) and glycoprotein hormone beta 5 (GPHB5). Here, we demonstrate that both subunits of CGH are expressed in the corticotroph cells of the human anterior pituitary, as well as in skin, retina, and testis. CGH activates the TSH receptor (TSHR); (125)I-CGH binding to cells expressing TSHR is saturable, specific, and of high affinity. In competition studies, unlabeled CGH is a potent competitor for (125)I-TSH binding, whereas unlabeled TSH does not compete for (125)I-CGH binding. Binding and competition analyses are consistent with the presence of two binding sites on the TSHR transfected baby hamster kidney cells, one that can interact with either TSH or CGH, and another that binds CGH alone. Transgenic overexpression of GPHB5 in mice produces elevations in serum T(4) levels, reductions in body weight, and proptosis. However, neither transgenic overexpression of GPHA2 nor deletion of GPHB5 produces an overt phenotype in mice. In vivo administration of CGH to mice produces a dose-dependent hyperthyroid phenotype including elevation of T(4) and hypertrophy of cells within the inner adrenal cortex. However, the distinctive expression patterns and binding characteristics of CGH suggest that it has endogenous biological roles that are discrete from those of TSH.

The role of genomic data in the discovery, annotation and evolutionary interpretation of the interferon-lambda family.

BACKGROUND: Type-I interferons, type-II interferons, and the IL-10 family are helical cytokines with similar three-dimensional folds. However, their homologous relationship is difficult to detect on the basis of sequence alone. We have previously described the discovery of the human type-III interferons (IFN lambda-1, -2, -3 or IL-29, IL-28A, IL-28B), which required a combination of manual and computational techniques applied to predicted protein sequences. PRINCIPAL FINDINGS: Here we describe how the use of gene structure analysis and comparative genomics enabled a more extensive understanding of these genes early in the discovery process. More recently, additional mammalian genome sequences have shown that there are between one and potentially nine copies of interferon lambda genes in each genome, and that several species have single exon versions of the interferon lambda gene. SIGNIFICANCE: The variable number of single exon type-I interferons in mammals, along with recently identified genes in zebrafish homologous to interferons allows a story of interferon evolution to be proposed. This model suggests that the gene duplications and single exon retrotransposons of mammalian type-III interferons are positively selected for within a genome. These characteristics are also shared with the fish interferons and could be responsible for the generation of the IL10 family and also the single exon type-I interferons.