RpuS/R Is a Novel Two-Component Signal Transduction System That Regulates the Expression of the Pyruvate Symporter MctP in Sinorhizobium fredii NGR234.

The SLC5/STAC histidine kinases comprise a recently identified family of sensor proteins in two-component signal transduction systems (TCSTS), in which the signaling domain is fused to an SLC5 solute symporter domain through a STAC domain. Only two members of this family have been characterized experimentally, the CrbS/R system that regulates acetate utilization in Vibrio and Pseudomonas, and the CbrA/B system that regulates the utilization of histidine in Pseudomonas and glucose in Azotobacter. In an attempt to expand the characterized members of this family beyond the Gammaproteobacteria, we identified two putative TCSTS in the Alphaproteobacterium Sinorhizobium fredii NGR234 whose sensor histidine kinases belong to the SLC5/STAC family. Using reverse genetics, we were able to identify the first TCSTS as a CrbS/R homolog that is also needed for growth on acetate, while the second TCSTS, RpuS/R, is a novel system required for optimal growth on pyruvate. Using RNAseq and transcriptional fusions, we determined that in S. fredii the RpuS/R system upregulates the expression of an operon coding for the pyruvate symporter MctP when pyruvate is the sole carbon source. In addition, we identified a conserved DNA sequence motif in the putative promoter region of the mctP operon that is essential for the RpuR-mediated transcriptional activation of genes under pyruvate-utilizing conditions. Finally, we show that S. fredii mutants lacking these TCSTS are affected in nodulation, producing fewer nodules than the parent strain and at a slower rate.

Correction: Deciphering the role of nuclear and cytoplasmic IKKα in skin cancer.

[This corrects the article DOI: 10.18632/oncotarget.8792.].

Deciphering the role of nuclear and cytoplasmic IKKα in skin cancer.

Nonmelanoma skin cancers (NMSC) are the most common human malignancies. IKKα is an essential protein for skin development and is also involved in the genesis and progression of NMSC, through mechanisms not fully understood. While different studies show that IKKα protects against skin cancer, others indicate that it promotes NMSC. To resolve this controversy we have generated two models of transgenic mice expressing the IKKα protein in the nucleus (N-IKKα mice) or the cytoplasm (C-IKKα mice) of keratinocytes. Chemical skin carcinogenesis experiments show that tumors developed by both types of transgenic mice exhibit histological and molecular characteristics that make them more prone to progression and invasion than those developed by Control mice. However, the mechanisms through which IKKα promotes skin tumors are different depending on its subcellular localization; while IKKα of cytoplasmic localization increases EGFR, MMP-9 and VEGF-A activities in tumors, nuclear IKKα causes tumor progression through regulation of c-Myc, Maspin and Integrin-α6 expression. Additionally, we have found that N-IKKα skin tumors mimic the characteristics associated to aggressive human skin tumors with high risk to metastasize. Our results show that IKKα has different non-overlapping roles in the nucleus or cytoplasm of keratinocytes, and provide new targets for intervention in human NMSC progression.

Classifying early-onset colorectal cancer according to tumor location: new potential subcategories to explore.

Early-onset Colorectal Cancer (ECRC) represents a significant and increasing proportion of Colorectal Cancer (CRC), but it is a heterogeneous entity that probably encompasses specific subclasses. On the premise that the carcinogenetic mechanism and progression of CRC may differ with location, we analyzed molecular and clinical characteristics of ECRC according to tumor location in order to identify more homogeneous subgroups of CRC. Right-sided ECRC is a subset in which most Lynch Syndrome cases are found, with earlier stages at diagnosis and better prognosis. At this location the CpG Island Methylator Phenotype (CIMP) is predominant and Chromosomal Instability (CI) is rare. Left-sided ECRC appears as a transitional or intermediate location, except for CI tumors, that seem to predominate at this location. Finally, rectal ECRC shows Microsatellite Stability, CIMP low-0 and low CI - with recurrent altered chromosomal regions in common with left-sided ECRC-, possibly in relation with Microsatellite And Chromosomal Stable tumors, but with an unexpected familial component and worse prognosis. All this suggest that the molecular basis of ECRC varies with tumor location, which could affect the clinical management of patients.