Prolactin (PRL) is released by the anterior pituitary and is important for the proper functioning of a wide variety of tissues, especially those of the reproductive system. PRL is expressed with temporal characteristics that suggest a high degree of regulation. Much of this can be attributed to the number and type of hypothalamic factors that act on the mammotrope population to modulate its synthesis and release. However, an equally important consideration in understanding the process of PRL regulation is the functional state of the mammotropes on which these factors act. Our measurement of PRL gene expression (PRL-GE) in individual living mammotropes revealed that cells with lower basal levels of PRL-GE were more responsive to thyrotropin releasing hormone than cells with higher levels indicating that the state of a target cell greatly impacts its response. Moreover, recent experiments revealed that these basal levels of PRL-GE are not constant, but oscillate in repetitive bursts or pulses. These oscillations reflect temporal changes in basal activity that would likely dictate the readiness of the cell to respond to secretagogues. Finally, these PRL-GE pulses were found to depend on a specific site in the PRL promoter termed an E-box that bind transcription factors associated with circadian gene regulation suggesting that elaboration of a pulse is a highly regulated and specifically timed cellular process. Taken together, it is clear that an understanding of PRL-GE pulses is critical to fully comprehend the regulation of PRL and its impact on the reproductive system. In this study, we propose to test the hypothesis that """"""""pulses of PRL-GE are fundamental to the control of both basal and stimulated mammotrope function and consequently are an important facet of normal reproductive function"""""""". This will be accomplished by addressing three SPECIFIC AIMS: I) to determine whether basal pulse patterns of PRL-GE and secretion in individual cells are fixed or change with varying reproductive state, II) to elucidate the relationship between pulses of PRL-GE and hypothalamic secretagogue action (i.e., stimulatory or inhibitory) in single mammotropes, and III) to identify the molecular processes that underlie pulsatile PRL- GE in mammotropes. Information gained from these studies will provide important insight into the role of this fundamental aspect of PRL expression and should contribute markedly to our understanding of the treatment of hyper or hypoprolactinemic conditions that impact reproduction.
| Bose, Sudeep; Boockfor, Fredric R (2010) Episodes of prolactin gene expression in GH3 cells are dependent on selective promoter binding of multiple circadian elements. Endocrinology 151:2287-96 |
