The promoter of Raet1, suggesting a direct regulation of Rae-1 expression by retinoic acid (RA) (93). Subsequently, treatment of hepatocellular carcinoma cells with RA was also found to induce the expression of MICA and MICB (73). Additionally, the promoters of MICA and MICB include heat shock response elements, and MIC transcripts can be induced in stressed cells (94). Adenovirus E1A oncogene was also shown to upregulate NKG2D ligands on mouse and human cell lines (95). Lastly, the transcription aspect AP-1, that is involved in tumorigenesis and cellular tension responses, was located to regulate Raet1 via the JunB subunit (96). Presently, transcriptional regulation of the genes encoding NKG2D ligands in humans and mice are poorly understood and this represents a crucial region for future investigation. D2 Receptor Inhibitor manufacturer Post-transcriptional and post-translational regulation Different mechanisms are accountable for the post-transcriptional regulation of NKG2D ligands. Stern-Ginossar et al. identified a group of endogenous cellular microRNAs (miRNAs) that bound towards the 3′-UTR (untranslated region) of MICA and MICB (97) and repressed their translation. Moreover, Yadav et al. identified 4 miRNAs that suppressed MICA expression (98). In accordance with these findings, silencing of Dicer, a crucial protein within the miRNA processing pathway, leads to the upregulation of MICA and MICB (99). LTC4 Antagonist web However, within this study, upregulation of NKG2D ligands was found to be dependent around the DNA damage sensor ATM, therefore suggesting that upregulation of NKG2D ligands in the absence of Dicer may be resulting from genotoxic anxiety along with the absence of regulatory miRNAs. In mouse cells lacking Dicer, upregulation of Rae-1 is often observed on splenocytes (N. Bezman, unpublished observation). Interestingly, HCMV was located to encode a viral miRNA, hcmv-miR-UL112, that competed with endogenous miRNA for binding to MICA and MICB 3′-UTR, hence repressing the translation of these ligands (one hundred). Recently, Nice et al. elegantly showed that MULT1 protein undergoes ubiquitination dependent on the lysines in its cytoplasmic tail, resulting in its rapid degradation (101). Ubiquitination was decreased in response to heat shock or UV irradiation, hence allowing cell surface expression of MULT1. Thus, heat shock operates on two levels: it increases the transcription of human MICA and MICB ligands, and it increases mouse MULT1 protein expression by decreasing its ubiquitination. Genotoxic tension did not impact MULT1 ubiquitination, illustrating the truth that various stimuli regulate NKG2D ligands differently.Immunol Rev. Author manuscript; offered in PMC 2011 May perhaps 1.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptChampsaur and LanierPageWhether other ligands with lengthy cytoplasmic tails are similarly regulated has not yet been investigated. The presence of multiple lysines within the cytoplasmic tail of H60a, H60b, MICA, MICB, and RAET-1G suggests that this translational handle mechanism could be applied by other NKG2D ligands. Interestingly, Thomas et al. have not too long ago described the capacity on the KSHV (Kaposi’s sarcoma-associated herpesvirus)-encoded E3 ubiquitin ligase K5 to downregulate cell surface expression of MICA and MICB (102). In this case, ubiquitination resulted within the redistribution of MICA to the plasma membrane, as opposed to its targeting to degradation as observed with MULT1. Since ubiquitination is dependent on motifs inside the cytoplasmic domains with the.