Description of Research Expertise

Research Interests
Signal transduction, proliferation, differentiation, apoptosis.

Key words: signal transduction, proliferation, differentiation, apoptosis, Ras, Rap1, cAMP.

Description of Research
Dr. Meinkoth's laboratory is interested in normal and aberrant growth regulation in thyroid follicular cells, specialized epithelial cells that synthesize, secrete and store thyroid hormone. Thyrotropin or TSH, the physiological regulator of thyroid cell proliferation, differentiation and survival, elicits many of its effects through the ubiquitous second messenger, cAMP. In addition to activating PKA, cAMP activates small G proteins, specifically Ras and Rap1 in thyroid cells. The contributions of PKA, Ras and Rap1 to the regulation of cell proliferation, differentiation and survival are under investigation.

Ras mutations occur at high frequency in thyroid tumors where alterations in H-, K- and N-Ras have been identified. B-Raf mutations are also prevalent in thyroid tumors. Stable expression of oncogenic Ras in thyroid cells confers TSH-independent proliferation, induces dramatic morphological alterations and extinguishes differentiated gene expression. In contrast, acute expression of oncogenic Ras stimulates aberrant cell cycle progression and apoptosis. The molecular mechanism through which Ras deregulates cell cycle progression and stimulates apoptosis is under investigation. Identifying the secondary changes that transpire to allow the survival of cells expressing activated Ras is an area of active interest.

TSH activates Rap1 through a cAMP-dependent, PKA-independent signaling pathway. PKA phosphorylates Rap1, an event that may be required for downstream signaling. Using selective activators of EPAC, a Rap-specific guanine nucleotide exchange factor, and of PKA, the individual contributions of cAMP and PKA to the regulation of Rap1 activity and signaling are being investigated.