Role and regulation of the high mobility group protein p8 in gonadotrope development, function, and tumorigenesis

Gonadotrope cells of the anterior pituitary gland produce and secrete two hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These two hormones increase the production of germ cells and the steroid hormones estrogen and testosterone in the ovaries and testes. Therefore, gonadotropes are critical to maintaining reproductive health. Previously, we have shown that the protein p8 is required for expression of the LHbeta subunit gene in the gonadotrope-derived LbetaT2 cell line. In addition, p8 is required for the tumor forming ability of a number of cells, including gonadotrope tumor-derived cells. As such, the goals of these studies were threefold: (1) to assess the impact of loss of p8 on gonadotrope function and reproductive health in a p8-knockout mouse model, (2) to determine the mechanism by which p8 facilitates tumor formation in gonadotrope tumor-derived cells, and (3) to determine the factor(s) controlling p8 expression in gonadotropes. Using the p8-knockout mouse line, we have found that p8 is required for proper temporal expression of LHbeta in gonadotropes and proper temporal sexual maturation of female mice, which we define as the presence of corpora lutea (CL) in the ovaries. p8 is not required for proper testicular development, but is required for maintenance of sperm production later in life; male p8-knockout mice develop a testicular phenotype similar to the human Sertoli-Cell-Only Syndrome by 10 months of age. In gonadotrope tumor-derived cells, we have found that p8 is required for tumor formation. p8 expression is associated with continued cell proliferation in stressful conditions that cause cells with knocked down p8 expression to enter a senescence-like state. p8 may allow for continued cell proliferation by decreasing expression of a group of cell cycle inhibitory proteins, p21, p27, and p57, as expression of all three factors is decreased in p8-expressing cells. Since p8 expression is required for proper gonadotrope function during development and is also linked to gonadotrope tumor formation, understanding the mechanisms controlling p8 expression in the gonadotrope is critical. To that end, we have found that the protein activating transcription factor 4 (ATF4) binds the p8 promoter and increased promoter activity in gonadotrope-derived LbetaT2 cells.