Expression of MHC class I is dynamically regulated in response to a variety of stimuli. Agents such as TNF and interferon are well known inducers of class I transcription. In contrast, thyroid stimulating hormone (TSH) specifically reduces class I gene transcription in thyrocytes; this down-regulation is cAMP-mediated. Whereas previous studies in the laboratory have focused on the mechanisms of TSH-mediated repression, recent studies are examining the molecular basis of interferon-mediated induction through the transcriptional co-activator CIITA. The CIITA co-activator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. Class I promoter activation by CIITA requires both the downstream core promoter and upstream sequences. Activation is absolutely dependent on the upstream CRE, located between -100 and -107 bp, but is further enhanced by a series of upstream sequence elements. Interestingly, the DNA sequence requirements for CIITA mediated activation are distinct from those of constitutive transcription. Furthermore, the transcription factor requirements for CIITA activation are also distinct from those of constitutive transcription: constitutive transcription requires TAFII250 whereas CIITA activation does not. Of particular interest, we have found that CIITA contains an intrinsic acetyl transferase (AT) activity that maps to a region within the N-terminal segment of CIITA, between amino acids 36 and 132. This AT activity is regulated by the C-terminal GTP-binding domain. CIITA-mediated transactivation depends on the AT activity.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009285-14
Application #
6433153
Study Section
(EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2000
Total Cost
Indirect Cost
Name
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