Chorionic gonadotropin (CG) and luteinizing hormone (LH) are critical for stimulation of steroidogenesis in human reproductive physiology. LH is produced by the anterior pituitary and CG is produced by the placenta to maintain pregnancy. CG is also of interest because it is produced ectopically in many tumors. These hormones are members of a family of glycoprotein hormones, including thyroid stimulating hormone and follical stimulating hormone, all of which share a common Alpha subunit but have distinct Beta subunits. In the proposed studies, the cloned LH and CG genes will be utilized to investigate the mechanisms involved in the regulation of these genes in physiology and tumorigenesis. First, additional structural features of these genes will be determined to provide information necessary for the subsequent studies. Secondly, differential expression of the several CG Beta-subunit genes in the placenta and in CG-expressing tumor cell lines will be characterized, as well as the effects on these genes of hormones, factors and second messengers (cyclic AMP, GnRH, Ca++, phorbol esters and steroid hormones). Thirdly, the cloned genes will be transferred to various cell types to determine whether elements contained in the cloned segments regulate either tissue-specificity or the hormone responsiveness of these genes. In cases where influences are found, mutated or hybrid genes will be constructed to identify the location of the responsive sequences. Finally, to investigate the development of ectopic hormone expression in tumorigenesis and to identify potential controlling elements, cells will be transformed with specific oncogenes, viruses or mitogens to determine whether ectopic CG expression can be reconstituted in cell culture. These studies should provide information relevant to the elucidation of the mechanisms of control of LH and CG expression important for understanding both human reproductive physiology and abnormal gene regulation in malignancy.
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