Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

BACKGROUND: Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to address this question. METHODS: Twenty-three cell lines of diverse origin and NRF2-pathway mutational status were used to determine the relationship between AKR expression and NRF2 activity. AKR expression was evaluated in lung cancer biopsies and Cancer Genome Atlas (TCGA) and Oncomine data sets. RESULTS: AKRs were expressed at a high basal level in cell lines carrying mutations in the NRF2 pathway. In non-mutant cell lines, co-ordinate induction of AKRs was consistently observed following activation of NRF2. Immunohistochemical analysis of lung tumour biopsies and interrogation of TCGA data revealed that AKRs are enriched in both squamous cell carcinomas (SCCs) and adenocarcinomas that contain somatic alterations in the NRF2 pathway but, in the case of SCC, AKRs were also enriched in most other tumours. CONCLUSIONS: An AKR biomarker panel can be used to determine NRF2 status in tumours. Hyperactivation of the NRF2 pathway is far more prevalent in lung SCC than previously predicted by genomic analyses

Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection

Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein-protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate CtIP proteins is essential for KLHL15-binding; its mutation blocks KLHL15-dependent CtIP ubiquitination and degradation. Consequently, DNA-end resection is strongly attenuated in cells overexpressing KLHL15 but amplified in cells either expressing a CtIP-FRY mutant or lacking KLHL15, thus impacting the balance between HR and NHEJ. Collectively, our findings underline the key importance and high complexity of CtIP modulation for genome integrity

Measurements of branching fractions for B^+ → p^+γ, B^0 → p^0γ, and B^0 → ωγ

We present branching fraction measurements for the radiative decays B^+ → ρ^+ γ, B^0 → ρ^0 γ, and B^0 → ωγ. The analysis is based on a data sample of 465 × 10^6 B[overline B] events collected with the BABAR detector at the PEP-II asymmetric-energy B Factory located at the Stanford Linear Accelerator Center. We find [script B](B^+ → ρ^+ γ) = (1.20_(-0.37)^(+0.42) ± 0.20) × 10^(-6), [script B](B^0 → ρ^0γ) = (0.97_(-0.22)^(+0.24) ± 0.06) × 10^(-6), and a 90% C.L. upper limit [script B](B^0 → ωγ) < 0.9 × 10^(-6), where the first error is statistical and the second is systematic. We also measure the isospin-violating quantity Γ(B^+ → ρ^+ γ)/2Γ(B^0 → ρ^0γ)-1 = -0.43_(-0.22)^(+0.25)±0.10

Evidence for the decay X(3872) -> J/ψω

We present a study of the decays B-0,B-+ -> J/psi pi(+)pi(-)pi K-0(0,+), using 467 x 106 B (B) over bar pairs recorded with the BABAR detector. We present evidence for the decay mode X(3872) -> J/psi omega, with product branching fractions B(B+ -> X(3872K(+)) x B(X(3872) -> J/psi omega) = [0.6 +/- 0.2(stat) +/- 0.1(syst)] x 10(-5), and B(B-0 -> X(3872)K-0) x B(X(3872) -> J/psi omega) = [0.6 +/- 0.3(stat) +/- 0.1(syst)] x 10(-5). A detailed study of the pi(+) pi(-) pi(0) mass distribution from X(3872) decay favors a negative-parity assignment

RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma

RNA-binding proteins provide a new layer of posttranscriptional regulation of RNA during cancer progression. We identified RNA-binding motif protein 47 (RBM47) as a target gene of transforming growth factor (TGF)-beta in mammary gland epithelial cells (NMuMG cells) that have undergone the epithelial-to-mesenchymal transition. TGF-beta repressed RBM47 expression in NMuMG cells and lung cancer cell lines. Expression of RBM47 correlated with good prognosis in patients with lung, breast and gastric cancer. RBM47 suppressed the expression of cell metabolism-related genes, which were the direct targets of nuclear factor erythroid 2-related factor 2 (Nrf2; also known as NFE2L2). RBM47 bound to KEAP1 and Cullin 3 mRNAs, and knockdown of RBM47 inhibited their protein expression, which led to enhanced binding of Nrf2 to target genomic regions. Knockdown of RBM47 also enhanced the expression of some Nrf2 activators, p21/CDKN1A and MafK induced by TGF-beta. Both mitochondrial respiration rates and the side population cells in lung cancer cells increased in the absence of RBM47. Our findings, together with the enhanced tumor formation and metastasis of xenografted mice by knockdown of the RBM47 expression, suggested tumor-suppressive roles for RBM47 through the inhibition of Nrf2 activity