CHROMOGRANINS IN NEUROENDOCRINE TUMOR CELLS

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The chromogranins are a family of immunologically distinct, secretory proteins that are expressed only in endocrine and neuronal cells that concentrate their secretory product in storage granules and release it upon stimulation. It is known that chromogranins are secreted at high rates by endocrine neoplasms, but the factors which regulate the secretion of chromogranins even under normal conditions are unknown. Furthermore, no function has yet been ascribed to the chromogranins. The long-term goal of this investigator is to understand the biological role of the chromogranins. Chromogranins may play an integral role in the aggregation and packing of peptide hormones into storage granules, but model systems to study this have been lacking until recently. The GH4C1 pituitary tumor cell line constitutes such a model system as the amount of prolactin diverted into a storage compartment can be hormonally regulated. Furthermore, the induction of prolactin storage is associated with an induction of chromogranin C storage. This is the first demonstration that any of the chromogranins can be regulated by hormones in cell culture system and suggests that chromogranin C functions intracellularly in some aspect of the diversion of prolactin into granules. The experiments described in this proposal are designed to further explore the relationship between prolactin and chromogranin C storage. The following questions will be answered by these studies: (1) Do hormones regulate the synthesis of chromogranin C in GH4C1 cells? (2) Does chromogranin C accumulate at the same rate as prolactin in GH4C1 cells under hormonal induction? (3) Are chromogranin C and prolactin found in the same cells and in the same granules in GH4C1 cell cultures? (4) What are the profiles of the acute release of chromogranin C and prolactin from GH4C1 cells? (5) What is the nature of the physicochemical interaction between chromogranin c and prolactin? These studies will be the unique properties of the GH4C1 cell line not only to gain fundamental knowledge of the factors which affect the production and cellular content of chromogranins, but also to establish the importance of chromogranins in hormone storage in this representative neuroendocrine cell line.