Direct action of growth hormone-releasing hormone agonist JI-38 on normal human fibroblasts: evidence from studies on cell proliferation and c-myc proto-oncogene expression

Growth hormone-releasing hormone (GHRH) is secreted by the hypothalamus and stimulates the release of growth hormone from the pituitary. Recent studies also indicate that in addition to its neuroendocrine function, GHRH may play a direct role in the proliferation of cancer cells, acting as growth factor for various human tumors. In the present study we investigated the effects of JI-38, an agonistic analog of GHRH, on the rate of proliferation of normal human diploid dermal fibroblasts (NHF) cultured in vitro. The effects of JI-38 on the levels of mRNA for c-myc proto-oncogene were also tested. Exposure to 10(-7) M JI-38 stimulated the rate of proliferation of early passage NHF by about 100%. Exposure of NHF cells to 10(-8)-5x10(-6) M JI-38 for 24 h resulted in about 0.5-3.5 fold increase in the levels of mRNA for c-myc proto-oncogene. The ability of JI-38 to stimulate the proliferation of NHF cells was abolished in cells cultured at late passage. Continuous exposure to 10(-7) M JI-38, over 6-7 passages (15-20 population doublings), progressively reduced the rate of proliferation of NHF compared with cells exposed to medium alone, indicating that GHRH agonist acted as a growth inhibitor. Our results suggest that at certain developmental stages, GHRH may act on various tissues, stimulating cell proliferation.     

Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution

Considerable progress has been made in understanding the physiological basis for variation in the life-history patterns of animals, particularly with regard to the roles of oxidative stress and hormonal regulation. However, an underappreciated and understudied area that could play a role in mediating inter- and intraspecific variation of life history is endoplasmic reticulum (ER) stress, and the resulting unfolded protein response (UPR^ER). ER stress response and the UPR^ER maintain proteostasis in cells by reducing the intracellular load of secretory proteins and enhancing protein folding capacity or initiating apoptosis in cells that cannot recover. Proper modulation of the ER stress response and execution of the UPR^ER allow animals to respond to intracellular and extracellular stressors and adapt to constantly changing environments. ER stress responses are heritable and there is considerable individual variation in UPR^ER phenotype in animals, suggesting that ER stress and UPR^ER phenotype can be subjected to natural selection. The variation in UPR^ER phenotype presumably reflects the way animals respond to ER stress and environmental challenges. Most of what we know about ER stress and the UPR^ER in animals has either come from biomedical studies using cell culture or from experiments involving conventional laboratory or agriculturally important models that exhibit limited genetic diversity. Furthermore, these studies involve the assessment of experimentally induced qualitative changes in gene expression as opposed to the quantitative variations that occur in naturally existing populations. Almost all of these studies were conducted in controlled settings that are often quite different from the conditions animals experience in nature. Herein, we review studies that investigated ER stress and the UPR^ER in relation to key life-history traits including growth and development, reproduction, bioenergetics and physical performance, and ageing and senescence. We then ask if these studies can inform us about the role of ER stress and the UPR^ER in mediating the aforementioned life-history traits in free-living animals. We propose that there is a need to conduct experiments pertaining to ER stress and the UPR^ER in ecologically relevant settings, to characterize variation in ER stress and the UPR^ER in free-living animals, and to relate the observed variation to key life-history traits. We urge others to integrate multiple physiological systems and investigate how interactions between ER stress and oxidative stress shape life-history trade-offs in free-living animals.