Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. The HO products carbon monoxide and bilirubin not only provide antioxidant cytoprotection, but also have potent anti-inflammatory and immunomodulatory functions. Although HO-1 has previously been shown to be induced by various stimuli via activation of the p38 MAPK signaling pathway, the role of this protein kinase for HO-1 gene regulation is largely unknown. In the present study, it is demonstrated that pharmacological inhibitors of p38 induced HO-1 expression in monocytic cells. Moreover, basal HO-1 gene expression levels were markedly higher in untreated murine embryonic fibroblasts (MEF) from p38α−/− mice compared with those from wild-type mice. Transfection studies with luciferase reporter gene constructs indicate that increased HO-1 gene expression via inhibition of p38 was mediated by the transcription factor Nrf2, which is a central regulator of the cellular oxidative stress response. Accordingly, inhibitors of p38 induced binding of nuclear proteins to a Nrf2 target sequence of the HO-1 promoter, but did not affect HO-1 protein expression and promoter activity in Nrf2−/− MEF. Genetic deficiency of p38 led to enhanced phosphorylation of ERK and increased cellular accumulation of reactive oxygen species. In addition, pharmacological blockage of ERK and scavenging of reactive oxygen species with N-acetylcysteine reduced HO-1 gene expression in p38−/− MEF, respectively. Taken together, it is demonstrated that pharmacological inhibition and genetic deficiency of p38 induce HO-1 gene expression via a Nrf2-dependent mechanism in monocytic cells and MEF.

Transcription by eukaryotic RNA polymerases (Pols) II and III and archaeal Pol requires structurally-related general transcription factors TFIIB, Brf1 and TFB, respectively, which are essential for polymerase recruitment and initiation events. A TFIIB-like protein was not evident in the Pol I basal transcription machinery. We report that TAF1B, a subunit of Pol I basal transcription factor SL1, is structurally related to TFIIB/TFIIB-like proteins, through predicted Nterminal Zn-ribbon and cyclin-like fold domains. SL1, essential for Pol I recruitment to the ribosomal RNA gene promoter, also has an essential post-polymerase recruitment role, operating through TAF1B. Therefore, a TFIIB-related protein is implicated in pre-initiation complex assembly and post-polymerase recruitment events in Pol I transcription, underscoring the parallels between eukaryotic Pol I, II and III and archaeal transcription machineries.Transcription by the cellular RNA polymerases (Pols) requires general transcription factors (GTFs) for promoter recognition, pre-initiation complex (PIC) formation and initiation. Distinct Pols synthesize the major ribosomal RNAs (Pol I), the messenger RNAs (Pol II) and the small nuclear and transfer RNAs (Pol III) in eukaryotes, whereas a single Pol directs transcription in archaea(1). Basal transcription by Pols II and III and archaeal Pol requires the structurally-related GTFs TFIIB(2-5), Brf1(6, 7) and TFB(8, 9), respectively. In bacteria, sigma factor performs some TFIIB functions and shows topological similarities in association with its Pol(4, 5). TFIIB/TFIIB-like proteins interact with TBP, polymerase and DNA in the PIC and are pivotal in early transcription events, including polymerase recruitment to promoters and post-recruitment events leading to transcription start-site selection, initiation and promoter escape. Given the evolutionary conservation of TFIIB-like proteins and their essential roles in transcription by eukaryotic Pols II and III and archaeal Pol, the Pol I basal transcription machinery is predicted to include a TFIIB-like component.Pol I basal transcription factor SL1 is a complex of TBP and TBP-associated factors(10-12), essential for recruitment of Pol I to the human rDNA promoter(13-15). Using HHpred, a server for protein remote homologue detection and structure prediction(16), we discovered that the TAF1B (TBP-associated factor 1B/TAF I 63) subunit of human SL1 is structurally similar to TFIIB, having the signature N-terminal Zn-ribbon and core domain with two potential cyclin-like folds (Fig. 1, Fig. S1, Tables S1, S2). The structural similarity, conserved throughout TAF1B orthologues from human TAF1B to yeast Core Factor subunit Rrn7(17), extends to Brf1, Brf2 and TFB and to plant TFIIB-like proteins such as pBrp, which is important for Pol I transcription(18) (Fig. S2, Table S1). TAF1B orthologues contain a C-terminal domain ( Fig. S3) with no counterpart in TFIIB (Fig. 1, Fig. S1 Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts distinct fr...

MicroRNAs (miRNAs) are important modulators of eukaryotic gene expression. By targeting protein coding transcripts, miRNAs influence the cellular transcriptome and proteome, thus helping to determine cell fate. MiRNAs have emerged as crucial molecules in cancer research, in which recent studies have linked erratic expression of miRNAs to carcinogenesis and have provided solid evidence for their potential in cancer therapy. This review briefly summarises the recent knowledge on the involvement of miRNAs in tumourigenesis and reviews current studies on the therapeutic strategies and advances in the delivery of miRNAs.