Control of growth hormone synthesis.

A large body of research, primarily in the rodent and human species, has elucidated many of the details regarding the control of GH synthesis and release. Cell type-specific transcriptional control has been identified as the main mechanism of the somatotroph-specific expression of GH. The recent detailed analysis in rodents and humans of a highly specific transcriptional activator protein, PIT-1, has opened several new areas of study. This is especially true for research in the farm animal species, where PIT-1 has been cloned and its binding elements on the GH gene are being investigated in a number of economically important species. Genetic and biochemical analyses of PIT-1 and other GH regulators have shown the central role of PIT-1 not only in the cell-autonomous stimulation of GH gene transcription, but also in the participation of PIT-1 in the response at the GH gene to exogenous hormones such as RA and TH. PIT-1 has been implicated in the proliferative development of the pituitary itself, in the maintenance of anterior pituitary cell types once cell types are defined, and in the mechanism by which the hypothalamic signal for GH release is transduced. However, PIT-1 by itself does not activate the GH gene, so that additional unknown factors exist that need to be identified to fully understand the cell type-specific activation of the GH gene. In addition, GH gene regulatory elements acting through well-characterized systems such as TH have seemingly different effects; the specific context of the regulatory elements relative to the promoter elements appear to be crucial. These contextual details of GH gene regulation are not well understood for any species and need to be further studied to be able to make predictions for particular elements and regulatory mechanisms across species. The regulation of the pulsatile secretion of GH by GHRH and SRIH is reasonably well understood after the cloning and analysis of the two releasing factors and their receptors. Modification or manipulation of the pathways involved in the regulation of GH secretion is a potential means of enhancing the lean tissue growth of meat animals. However, further understanding of the systems controlling the in vivo release of GH is needed before such manipulations are likely to be productive. Several other research questions regarding the control of GH expression and release remain to be answered. What is the biochemical connection between exogenous signal transduction (i.e., GRH/GHRH-R, TR, ER, RAR) and PIT-1 at the GH gene? Are there additional coactivators or repressors of GH that respond to cAMP levels? Do ubiquitous regulatory factors such as GHF-3 and Zn-15, identified thus far only in the rat, exist in humans or livestock? Zn-15 is expected to be found in many mammalian species, because its recognition sequence between the PIT-1 binding sites is highly conserved across mammals (Figure 2). What is the mechanism causing GH levels to drop during aging? Does PIT-1 expression decrease during the lifespan of animals? Is it possible to increase GH gene expression within target tissues by directing the expression of PIT-1 to these tissues via transgenesis, or are other factors limiting in peripheral tissues so that the lack of PIT-1 expression is not the deciding factor? Finally, is there genetic variation in the expression of GHRH and/or SRIH or in their respective receptors? These questions are relevant to and could be investigated in several of the livestock species.