The promoter of Raet1, suggesting a direct regulation of Rae-1 expression by retinoic acid (RA)

The promoter of Raet1, suggesting a direct regulation of Rae-1 expression by retinoic acid (RA) (93). Subsequently, remedy of hepatocellular carcinoma cells with RA was also located to induce the expression of MICA and MICB (73). Moreover, the promoters of MICA and MICB include heat shock response components, and MIC transcripts could 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 factor AP-1, that is involved in tumorigenesis and cellular tension IDH1 Inhibitor supplier responses, was identified to regulate Raet1 by means of the JunB subunit (96). Presently, transcriptional regulation with the genes encoding NKG2D ligands in humans and mice are poorly understood and this represents a crucial area for future investigation. Post-transcriptional and post-translational regulation Different mechanisms are responsible for the post-transcriptional regulation of NKG2D ligands. Stern-Ginossar et al. identified a group of endogenous cellular microRNAs (miRNAs) that bound for the 3′-UTR (untranslated area) of MICA and MICB (97) and repressed their translation. Moreover, Yadav et al. identified four miRNAs that suppressed MICA expression (98). In accordance with these findings, silencing of Dicer, a crucial protein inside the miRNA processing pathway, results in the upregulation of MICA and MICB (99). However, within this study, upregulation of NKG2D ligands was located to become dependent on the DNA harm sensor ATM, therefore suggesting that upregulation of NKG2D ligands in the absence of Dicer could be as a Kainate Receptor Agonist Compound result of genotoxic pressure 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 In mouse cells lacking Dicer, upregulation of Rae-1 is often observed on splenocytes (N. Bezman, unpublished observation).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 found 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 those ligands (one hundred). Recently, Good et al. elegantly showed that MULT1 protein undergoes ubiquitination dependent on the lysines in its cytoplasmic tail, resulting in its speedy degradation (101). Ubiquitination was reduced in response to heat shock or UV irradiation, thus allowing cell surface expression of MULT1. Therefore, 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 pressure didn’t impact MULT1 ubiquitination, illustrating the fact that various stimuli regulate NKG2D ligands differently.Immunol Rev. Author manuscript; readily available in PMC 2011 May possibly 1.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptChampsaur and LanierPageWhether other ligands with long cytoplasmic tails are similarly regulated has not yet been investigated. The presence of various lysines in the cytoplasmic tail of H60a, H60b, MICA, MICB, and RAET-1G suggests that this translational manage mechanism may well be utilized by other NKG2D ligands. Interestingly, Thomas et al. have not too long ago described the capacity of 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 in the redistribution of MICA to the plasma membrane, as opposed to its targeting to degradation as observed with MULT1. Mainly because ubiquitination is dependent on motifs inside the cytoplasmic domains in the.