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Nagel, Remco; Semenova, Ekaterina A; Berns, Anton
doi: 10.15252/embr.201643030pmid: 27702988
Historically, cancers have been treated with chemotherapeutics aimed to have profound effects on tumor cells with only limited effects on normal tissue. This approach was followed by the development of small‐molecule inhibitors that can target oncogenic pathways critical for the survival of tumor cells. The clinical targeting of these so‐called oncogene addictions, however, is in many instances hampered by the outgrowth of resistant clones. More recently, the proper functioning of non‐mutated genes has been shown to enhance the survival of many cancers, a phenomenon called non‐oncogene addiction. In the current review, we will focus on the distinct non‐oncogenic addictions found in cancer cells, including synthetic lethal interactions, the underlying stress phenotypes, and arising therapeutic opportunities.
Li, Minxing; Cole, Francesca; Patel, Dharm S; Misenko, Sarah M; Her, Joonyoung; Malhowski, Amy; Alhamza, Ali; Zheng, Haiyan; Baer, Richard; Ludwig, Thomas; Jasin, Maria; Nussenzweig, André; Serrano, Lourdes; Bunting, Samuel F
Candeias, Marco M; Hagiwara, Masatoshi; Matsuda, Michiyuki
doi: 10.15252/embr.201541956pmid: 27702985
Wild‐type p53 functions as a tumour suppressor while mutant p53 possesses oncogenic potential. Until now it remains unclear how a single mutation can transform p53 into a functionally distinct gene harbouring a new set of original cellular roles. Here we show that the most common p53 cancer mutants express a larger number and higher levels of shorter p53 protein isoforms that are translated from the mutated full‐length p53 mRNA. Cells expressing mutant p53 exhibit “gain‐of‐function” cancer phenotypes, such as enhanced cell survival, proliferation, invasion and adhesion, altered mammary tissue architecture and invasive cell structures. Interestingly, Δ160p53‐overexpressing cells behave in a similar manner. In contrast, an exogenous or endogenous mutant p53 that fails to express Δ160p53 due to specific mutations or antisense knock‐down loses pro‐oncogenic potential. Our data support a model in which “gain‐of‐function” phenotypes induced by p53 mutations depend on the shorter p53 isoforms. As a conserved wild‐type isoform, Δ160p53 has evolved during millions of years. We thus provide a rational explanation for the origin of the tumour‐promoting functions of p53 mutations.
Torii, Satoru; Yoshida, Tatsushi; Arakawa, Satoko; Honda, Shinya; Nakanishi, Akira; Shimizu, Shigeomi
doi: 10.15252/embr.201642565pmid: 27670885
Autophagy is an evolutionary conserved process that degrades subcellular constituents. Unlike starvation‐induced autophagy, the molecular mechanism of genotoxic stress‐induced autophagy has not yet been fully elucidated. In this study, we analyze the molecular mechanism of genotoxic stress‐induced autophagy and identify an essential role of dephosphorylation of the Unc51‐like kinase 1 (Ulk1) at Ser637, which is catalyzed by the protein phosphatase 1D magnesium‐dependent delta isoform (PPM1D). We show that after exposure to genotoxic stress, PPM1D interacts with and dephosphorylates Ulk1 at Ser637 in a p53‐dependent manner. The PPM1D‐dependent Ulk1 dephosphorylation triggers Ulk1 puncta formation and induces autophagy. This happens not only in mouse embryonic fibroblasts but also in primary thymocytes, where the genetic ablation of PPM1D reduces the dephosphorylation of Ulk1 at Ser637, inhibits autophagy, and accelerates apoptosis induced by X‐ray irradiation. This acceleration of apoptosis is caused mainly by the inability of the autophagic machinery to degrade the proapoptotic molecule Noxa. These findings indicate that the PPM1D–Ulk1 axis plays a pivotal role in genotoxic stress‐induced autophagy.
Bonomi, Hernán R; Toum, Laila; Sycz, Gabriela; Sieira, Rodrigo; Toscani, Andrés M; Gudesblat, Gustavo E; Leskow, Federico C; Goldbaum, Fernando A; Vojnov, Adrián A; Malamud, Florencia
doi: 10.15252/embr.201541691pmid: 27621284
Allu, Annapurna Devi; Brotman, Yariv; Xue, Gang‐Ping; Balazadeh, Salma
doi: 10.15252/embr.201642197pmid: 27632992
Responses to pathogens, including host transcriptional reprogramming, require partially antagonistic signalling pathways dependent on the phytohormones salicylic (SA) and jasmonic (JA) acids. However, upstream factors modulating the interplay of these pathways are not well characterized. Here, we identify the transcription factor ANAC032 from Arabidopsis thaliana as one such regulator in response to the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pst). ANAC032 directly represses MYC2 activation upon Pst attack, resulting in blockage of coronatine‐mediated stomatal reopening which restricts entry of bacteria into plant tissue. Furthermore, ANAC032 activates SA signalling by repressing NIMIN1, a key negative regulator of SA‐dependent defence. Finally, ANAC032 reduces expression of JA‐responsive genes, including PDF1.2A. Thus, ANAC032 enhances resistance to Pst by generating an orchestrated transcriptional output towards key SA‐ and JA‐signalling genes coordinated through direct binding of ANAC032 to the MYC2, NIMIN1 and PDF1.2A promoters.
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doi: 10.15252/embr.201642497pmid: 27670884
BRCA1 mutations strongly predispose affected individuals to breast and ovarian cancer, but the mechanism by which BRCA1 acts as a tumor suppressor is not fully understood. Homozygous deletion of exon 2 of the mouse Brca1 gene normally causes embryonic lethality, but we show that exon 2‐deleted alleles of Brca1 are expressed as a mutant isoform that lacks the N‐terminal RING domain. This “RING‐less” BRCA1 protein is stable and efficiently recruited to the sites of DNA damage. Surprisingly, robust RAD51 foci form in cells expressing RING‐less BRCA1 in response to DNA damage, but the cells nonetheless display the substantial genomic instability. Genomic instability can be rescued by the deletion of Trp53bp1, which encodes the DNA damage response factor 53BP1, and mice expressing RING‐less BRCA1 do not show an increased susceptibility to tumors in the absence of 53BP1. Genomic instability in cells expressing RING‐less BRCA1 correlates with the loss of BARD1 and a defect in restart of replication forks after hydroxyurea treatment, suggesting a role of BRCA1–BARD1 in genomic integrity that is independent of RAD51 loading.
Phytochromes constitute a major photoreceptor family found in plants, algae, fungi, and prokaryotes, including pathogens. Here, we report that Xanthomonas campestris pv. campestris (Xcc), the causal agent of black rot disease which affects cruciferous crops worldwide, codes for a functional bacteriophytochrome (XccBphP). XccBphP possesses an N‐terminal PAS2‐GAF‐PHY photosensory domain triad and a C‐terminal PAS9 domain as its output module. Our results show that illumination of Xcc, prior to plant infection, attenuates its virulence in an XccBphP‐dependent manner. Moreover, in response to light, XccBphP downregulates xanthan exopolysaccharide production and biofilm formation, two known Xcc virulence factors. Furthermore, the XccbphP null mutant shows enhanced virulence, similar to that of dark‐adapted Xcc cultures. Stomatal aperture regulation and callose deposition, both well‐established plant defense mechanisms against bacterial pathogens, are overridden by the XccbphP strain. Additionally, an RNA‐Seq analysis reveals that far‐red light or XccBphP overexpression produces genomewide transcriptional changes, including the inhibition of several Xcc virulence systems. Our findings indicate that Xcc senses light through XccBphP, eliciting bacterial virulence attenuation via downregulation of bacterial virulence factors. The capacity of XccBphP to respond to light both in vitro and in vivo was abolished by a mutation on the conserved Cys13 residue. These results provide evidence for a novel bacteriophytochrome function affecting an infectious process.