Inhibitor of Growth 3 (ING3) is a candidate tumor suppressor gene whose expression is lost in tumors such as hepatocellular carcinoma, head and neck squamous cell carcinoma and melanoma. In the ...present study, we show that ING3-depleted human cells and yeast cells deleted for its ortholog YNG2 are sensitive to DNA damage suggesting a conserved role in response to such stress. In human cells, ING3 is recruited to DNA double strand breaks and is required for ATM activation. Remarkably, in response to doxorubicin, ATM activation is dependent on ING3 but not on TIP60, whose recruitment to DNA breaks also depends on ING3. These events lead to ATM-mediated phosphorylation of NBS1 and the subsequent recruitment of RNF8, RNF168, 53BP1, and BRCA1, which are major mediators of the DNA damage response. Accordingly, upon genotoxic stress, DNA repair by non-homologous end joining (NHEJ) or homologous recombination (HR) were impaired in absence of ING3. Finally, immunoglobulin class switch recombination (CSR), a physiological mechanism requiring NHEJ repair, was impaired in the absence of ING3. Since deregulation of DNA double strand break repair is associated with genomic instability, we propose a novel function of ING3 as a caretaker tumor suppressor involved in the DNA damage signaling and repair.
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ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT ...or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability.
ING2 (Inhibitor of Growth 2) is a tumor suppressor gene that has been implicated in critical biological functions (cell-cycle regulation, replicative senescence, DNA repair and DNA replication), most ...of which are recognized hallmarks of tumorigenesis occurring in the cell nucleus. As its close homolog ING1 has been recently observed in the mitochondrial compartment, we hypothesized that ING2 could also translocate into the mitochondria and be involved in new biological functions. In the present study, we demonstrate that ING2 is imported in the inner mitochondrial fraction in a redox-sensitive manner in human cells and that this mechanism is modulated by 14-3-3η protein expression. Remarkably, ING2 is necessary to maintain mitochondrial ultrastructure integrity without interfering with mitochondrial networks or polarization. We observed an interaction between ING2 and mtDNA under basal conditions. This interaction appears to be mediated by TFAM, a critical regulator of mtDNA integrity. The loss of mitochondrial ING2 does not impair mtDNA repair, replication or transcription but leads to a decrease in mitochondrial ROS production, suggesting a detrimental impact on OXPHOS activity. We finally show using multiple models that ING2 is involved in mitochondrial respiration and that its loss confers a protection against mitochondrial respiratory chain inhibition in vitro. Consequently, we propose a new tumor suppressor role for ING2 protein in the mitochondria as a metabolic shift gatekeeper during tumorigenesis.
ING family genes (Inhibitor of Growth) are tumor suppressor genes that play a vital role in cell homeostasis. It has been shown that their expression is lost or diminished in many cancers and other ...diseases. The main mechanisms by which they are regulated in oncogenesis have not yet been fully elucidated. The involvement of non-coding RNAs (ncRNAs) and in particular microRNAs (miRNAs) in post-transcriptional gene regulation is well established. miRNAs are short sequences (18–25 nucleotides) that can bind to the 3 ′UTR sequence of the targeted messenger RNA (mRNA), leading to its degradation or translational repression. Interactions between the ING family and miRNAs have been described in some cancers but also in other diseases. The involvement of miRNAs in ING family regulation opens up new fields of investigation, particularly for targeted therapies. In this review, we will summarize the regulatory mechanisms at the RNA and protein level of the ING family and focus on the interactions with ncRNAs.
•INGs are tumor suppressor genes playing a crucial role in cell homeostasis.•Multiple mechanisms may be involved in INGs loss or downregulation.•INGs regulation is still unclear and can involve ncRNAs.•ncRNAs may play an important role in cancer and other disease notably through INGs regulation.
Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell ...lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.
Intrinsic or environmental stresses trigger the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), leading to ER stress. To cope with this, cells have evolved an adaptive ...mechanism named the unfolded protein response (UPR) which is hijacked by tumor cells to develop malignant features. Glioblastoma (GB), the most aggressive and lethal primary brain tumor, relies on UPR to sustain growth. We recently showed that IRE1 alpha (referred to IRE1 hereafter), 1 of the UPR transducers, promotes GB invasion, angiogenesis, and infiltration by macrophage. Hence, high tumor IRE1 activity in tumor cells predicts a worse outcome. Herein, we characterized the IRE1-dependent signaling that shapes the immune microenvironment toward monocytes/macrophages and neutrophils.
We used human and mouse cellular models in which IRE1 was genetically or pharmacologically invalidated and which were tested in vivo. Publicly available datasets from GB patients were also analyzed to confirm our findings.
We showed that IRE1 signaling, through both the transcription factor XBP1s and the regulated IRE1-dependent decay controls the expression of the ubiquitin-conjugating E2 enzyme UBE2D3. In turn, UBE2D3 activates the NFκB pathway, resulting in chemokine production and myeloid infiltration in tumors.
Our work identifies a novel IRE1/UBE2D3 proinflammatory axis that plays an instrumental role in GB immune regulation.
ING3 (Inhibitor of Growth 3) is a candidate tumor suppressor gene whose expression is lost in tumors. Aims: We want to identify and characterize new tumor suppresor functions for ING3. Methods: We ...conduct experiments in yeast and human cells depleted or not for ING3 and exposed to genotoxic agents. Results: - ING3-depleted human cells and yeast cells deleted for its ortholog YNG2 are sensitive to DNA damage suggesting a conserved role in response to such stress. - In human cells, ING3 is recruited to DNA double strand breaks and is required for ATM activation. - In response to doxorubicin, ATM activation is dependent on ING3 but not on TIP60, whose recruitment to DNA breaks also depends on ING3. - These events lead to ATM-mediated phosphorylation of NBS1 and of major mediators of the DNA damage response. - Upon genotoxic stress, DNA repair by Non Homologous End Joining (NHEJ) or Homologous Recombination (HR) were impaired in absence of ING3. - Immunoglobulin Class Switch Recombination (CSR), a physiological mechanism requiring NHEJ repair, was impaired in the absence of ING3. Conclusions: Since deregulation of DNA double strand break repair is associated with genomic instability, we propose a novel function of ING3 as a caretaker tumor suppressor involved in the DNA damage signaling and repair. Funding: A.M. was a recipient of a doctoral fellowship from La Ligue Contre le Cancer and Region Bretagne. R.P. & M.G. were recipients of from Ulysses “The France – Ireland Exchange Scheme”. N. Bigot was a recipient of ANR program (SAFE 2012) (ANR-11-RPIB-0012). C. References: Cell Death Differ. 2019 Feb 25. doi: 10.1038/s41418-019-0305-x. Epub ahead of print
The precipitation of α phase during ageing was investigated in the near-β titanium alloy Ti-17 considering either a fully βmetastable initial microstructure or a 35% αprimary + 65% βmetastable ...initial microstructure. In-situ electrical resistivity and high energy X-ray diffraction measurements revealed the influence of the initial microstructure, with different α morphologies (size and distribution of αprimary), as well as the heating rate on the precipitation sequences and kinetics following the decomposition of the β-metastable phase. Various amounts of metastable phases (ωisothermal and α″isothermal) precipitate in temperature ranges that increase with the heating rate. From temperatures about 500 °C, the orthorhombic α″isothermal structure evolved towards the hexagonal close-packed α as temperature increased. SEM microstructure characterisations showed that slow heating rates promoted a fine and dense α precipitate distribution through the formation of ωisothermal and/or α″isothermal, leading to higher hardness values. A higher heating rate restricted the precipitation of α″isothermal and shifted to the one of α at a higher temperature, leading to coarser precipitates. Furthermore, precipitation kinetics of α″isothermal/α were quicker considering an initial intragranular α precipitation as compared to α colonies.
•The α size and spatial distribution influence precipitation kinetics during ageing.•Precipitation sequences and their kinetics are affected by the heating rate.•Lower heating rates promote a refined and homogeneous distribution of α plates.•The crystal structure of α″isothermal tends toward the one of α.
The precipitation of α phase during ageing was investigated in the near-β titanium alloy Ti-17 considering either a fully βmetastable initial microstructure or a 35% αprimary + 65% βmetastable ...initial microstructure. In-situ electrical resistivity and high energy X-ray diffraction measurements revealed the influence of the initial microstructure, with different α morphologies (size and distribution of αprimary), as well as the heating rate on the precipitation sequences and kinetics following the decomposition of the β-metastable phase. Various amounts of metastable phases (ωisothermal and α″isothermal) precipitate in temperature ranges that increase with the heating rate. From temperatures about 500 °C, the orthorhombic α″isothermal structure evolved towards the hexagonal close-packed α as temperature increased. SEM microstructure characterisations showed that slow heating rates promoted a fine and dense α precipitate distribution through the formation of ωisothermal and/or α″isothermal, leading to higher hardness values. A higher heating rate restricted the precipitation of α″isothermal and shifted to the one of α at a higher temperature, leading to coarser precipitates. Furthermore, precipitation kinetics of α″isothermal/α were quicker considering an initial intragranular α precipitation as compared to α colonies.
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