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,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009285-13
Application #
6289251
Study Section
Special Emphasis Panel (EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Giuliani, C; Saji, M; Bucci, I et al. (2006) Transcriptional regulation of major histocompatibility complex class I gene by insulin and IGF-I in FRTL-5 thyroid cells. J Endocrinol 189:605-15
Howcroft, T Kevin; Weissman, Jocelyn D; Gegonne, Anne et al. (2005) A T lymphocyte-specific transcription complex containing RUNX1 activates MHC class I expression. J Immunol 174:2106-15
Lee, Maxwell P; Howcroft, Kevin; Kotekar, Aparna et al. (2005) ATG deserts define a novel core promoter subclass. Genome Res 15:1189-97
Mozes, E; Lovchik, J; Zinger, H et al. (2005) MHC class I expression regulates susceptibility to spontaneous autoimmune disease in (NZBxNZW)F1 mice. Lupus 14:308-14
Grassadonia, Antonino; Tinari, Nicola; Fiorentino, Bruno et al. (2004) The 90K protein increases major histocompatibility complex class I expression and is regulated by hormones, gamma-interferon, and double-strand polynucleotides. Endocrinology 145:4728-36
Howcroft, T Kevin; Raval, Aparna; Weissman, Jocelyn D et al. (2003) Distinct transcriptional pathways regulate basal and activated major histocompatibility complex class I expression. Mol Cell Biol 23:3377-91
Weissman, Jocelyn D; Raval, Aparna; Singer, Dinah S (2003) Assay of an intrinsic acetyltransferase activity of the transcriptional coactivator CIITA. Methods Enzymol 370:378-86
Raval, Aparna; Weissman, Jocelyn D; Howcroft, T Kevin et al. (2003) The GTP-binding domain of class II transactivator regulates its nuclear export. J Immunol 170:922-30