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Prieto, N.

Publications and source records attributed to Prieto, N..

2 recordsLinked to original sources

Drosophila male genitalia rotation depends on permissive remodeling of the posterior abdomen

One of the most characteristic morphogenetic processes in Drosophila is the 360{degrees} rotation of the male pupal genital disc. This movement is driven by the myosin Myo1D, whose expression in the genital disc is controlled by the Hox gene Abdominal-B. The rotation takes place in contact and relative to the posterior abdomen, yet the contribution of abdominal tissues has remained unclear. Here we show that normal genital disc circumrotation requires active remodeling of posterior abdominal larval epidermal cells that contact the rotating terminalia. Preventing apoptosis in these cells, or increasing EGFR signaling, delays their extrusion and results in incomplete rotation without altering rotational chirality. In parallel, elimination of Extracellular Matrix by Metalloproteinase 1 in these cells, although without leading to their extrusion, is also strictly required for genital disc circumrotation. Inhibition of this metalloproteinase activity leads to persistence of collagen IV and incomplete rotation, revealing an independent requirement for Extracellular Matrix clearance at the disc-abdomen interface. By contrast, genetic conditions that prevent formation or elimination of the male A7 segment do not necessarily impair genital disc rotation, demonstrating that A7 suppression and circumrotation are separable processes. These findings identify posterior abdominal tissue remodeling as an essential extrinsic requirement that enables genital disc circumrotation.

developmental biology↗

Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone

Alterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent {beta}-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to {beta}-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of {beta}-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to {beta}-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to {beta}-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to {beta}-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to {beta}-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations. HighlightsO_LIAberrant activation of NRF2 in non-small cell lung cancer promotes resistance to {beta}-lapachone via the antioxidant defense. C_LIO_LIInhibition of the thioredoxin-dependent system and superoxide dismutase 1 increase sensitivity to {beta}-lapachone treatment. C_LIO_LIMutations in the NRF2/KEAP1 pathway might serve as predictive biomarker for response to {beta}-lapachone in patients. C_LI

cancer biology↗