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). In addition, the promoters of MICA and MICB include heat shock response elements, and MIC transcripts might be induced in stressed cells (94). Adenovirus E1A oncogene was also shown to upregulate NKG2D MMP-1 Proteins MedChemExpress ligands on mouse and human cell lines (95). Lastly, the transcription factor AP-1, which can be involved in tumorigenesis and cellular strain responses, was discovered to regulate Raet1 by way of the JunB subunit (96). Presently, transcriptional regulation of your genes encoding NKG2D ligands in humans and mice are poorly understood and this represents an important area for future investigation. Post-transcriptional and post-translational regulation Several 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 towards the 3′-UTR (untranslated area) of MICA and MICB (97) and repressed their translation. In addition, Yadav et al. identified four miRNAs that suppressed MICA expression (98). In accordance with these findings, silencing of Dicer, a important protein inside the miRNA processing pathway, leads to the upregulation of MICA and MICB (99). Having said that, in this study, upregulation of NKG2D ligands was located to be dependent around the DNA harm sensor ATM, as a result suggesting that upregulation of NKG2D ligands in the absence of Dicer could possibly be as a result of genotoxic stress in addition to 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 In mouse cells lacking Dicer, upregulation of Rae-1 is often observed on splenocytes (N. Bezman, unpublished observation).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 discovered to encode a viral miRNA, hcmv-miR-UL112, that competed with endogenous miRNA for binding to MICA and MICB 3′-UTR, therefore repressing the translation of those ligands (100). Recently, Nice 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 lowered in response to heat shock or UV irradiation, therefore permitting cell surface expression of MULT1. Thus, heat shock operates on two levels: it Siglec-13 Proteins Recombinant Proteins increases the transcription of human MICA and MICB ligands, and it increases mouse MULT1 protein expression by decreasing its ubiquitination. Genotoxic stress didn’t have an effect on MULT1 ubiquitination, illustrating the fact that different stimuli regulate NKG2D ligands differently.Immunol Rev. Author manuscript; available in PMC 2011 May 1.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptChampsaur and LanierPageWhether other ligands with extended cytoplasmic tails are similarly regulated has not yet been investigated. The presence of many lysines inside the cytoplasmic tail of H60a, H60b, MICA, MICB, and RAET-1G suggests that this translational control mechanism may well be made use of by other NKG2D ligands. Interestingly, Thomas et al. have not too long ago described the capacity from the KSHV (Kaposi’s sarcoma-associated herpesvirus)-encoded E3 ubiquitin ligase K5 to downregulate cell surface expression of MICA and MICB (102). Within this case, ubiquitination resulted in the redistribution of MICA for the plasma membrane, instead of its targeting to degradation as observed with MULT1. For the reason that ubiquitination is dependent on motifs within the cytoplasmic domains in the.