RESPONSES OF MHC CLASS I GENES TO EXOGENEOUS STIMULI

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Expression of MHC class I is dynamically regulated in response to a variety of stimuli. While agents such as TNF and interferon are well known inducers of class I transcription, many other factors also affect expression. We have shown that thyroid stimulating hormone (TSH) specifically reduces class I gene transcription in thyrocytes; this down-regulation is cAMP-mediated. Three DNA elements have been shown to be targets of cAMP action. One of these is a complex element that contains a classical CRE and functions as a constitutive silencer. Regulation through the CRE is achieved by combinatorial interactions of tissue specific and general transcription factors, that bind to sequences overlapping the CRE, both 5 and 3. The tissue specific factor, TTF1, binds the element in the absence of cAMP, partially countering the silencer activity. Following cAMP, TTF1 activity decreases, resulting in increased silencer activity that is potentiated by the binding of TSEP-1, a Y-box binding protein that reduces class I transcription. The tissue specific factors, TTF1 and Pax 8, also regulate expression of thyroglobulin and the TSHR genes, establishing coordinate regulation of these genes. A second cAMP-response element has been mapped to a 30 bp element that partially overlaps the previously identified interferon response element, IRE. Thus, the class I IRE acts as an enhancer in response to interferon, but as a silencer in response to cAMP. Induction of class I promoter activity by interferon requires not only the IRE, but also the CRE. Thus, both cAMP and interferon function through common elements to achieve opposite effects. Furthermore, the effects of cAMP are mediated by PKA which induces the expression of the CREM-family member of transcription factors, ICER. ICER is a component of a complex that binds to both the CRE and IRE DNA sequence elements, forming higher-order enhanceosome- like structures. The third cAMP-responsive element has been identified at the basal promoter. In this case, the effect of cAMP is targetted to the initiation complex itself, and not to a single DNA sequence element. These studies have demonstrated that the dynamice regulation of class I gene expression requires a series of complex interactions involving multiple regulatory DNA sequence elements, coordinately interacting with common and tissue specific transcription factors. In addition, this regulatory system provides a mechanism for coordinate regulation of class I genes with tissue specific genes. - thyroid stimulating hormone, transcription, ICER,