The promoter of Raet1, suggesting a direct Cathepsin S Inhibitor review regulation of Rae-1 expression by retinoic acid (RA) (93). Subsequently, therapy 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 contain heat shock response elements, and MIC transcripts may be induced in stressed cells (94). Adenovirus E1A oncogene was also shown to upregulate NKG2D ligands on mouse and human cell lines (95). Ultimately, the transcription issue AP-1, which can be involved in tumorigenesis and cellular anxiety responses, was located to regulate Raet1 by way of the JunB subunit (96). Presently, transcriptional regulation of the 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 Various 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 for the 3′-UTR (untranslated area) of MICA and MICB (97) and repressed their translation. Additionally, Yadav et al. identified four miRNAs that suppressed MICA expression (98). In accordance with these findings, silencing of Dicer, a key protein within the miRNA processing pathway, leads to the upregulation of MICA and MICB (99). However, in this study, upregulation of NKG2D ligands was identified to become dependent on the DNA harm sensor ATM, hence suggesting that upregulation of NKG2D ligands in the absence of Dicer may possibly be on account of CaMK II Inhibitor medchemexpress genotoxic stress as well as the absence of regulatory miRNAs. In mouse cells lacking Dicer, upregulation of Rae-1 is frequently observed on splenocytes (N. Bezman, unpublished observation).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, as a result 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 fast degradation (101). Ubiquitination was lowered in response to heat shock or UV irradiation, thus enabling cell surface expression of MULT1. Hence, 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 anxiety didn’t affect MULT1 ubiquitination, illustrating the fact that unique stimuli regulate NKG2D ligands differently.Immunol Rev. Author manuscript; obtainable 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 a number of lysines within the cytoplasmic tail of H60a, H60b, MICA, MICB, and RAET-1G suggests that this translational control mechanism may possibly be applied by other NKG2D ligands. Interestingly, Thomas et al. have not too long ago described the capacity with 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 towards the plasma membrane, as opposed to its targeting to degradation as observed with MULT1. Due to the fact ubiquitination is dependent on motifs inside the cytoplasmic domains of the.
