Cet article analyse les données relatives aux mutations somatiques et constitutionnelles du gène TP53 contenues dans la base UMD TP53

TP53 Mutations in Human Cancer: Database Reassessment and Prospects for the Next Decade

Leroy, Bernard ; Anderson, Martha ; Soussi, Thierry

More than 50% of human tumors carry TP53 gene mutations and in consequence more than 45,000 somatic and germline mutations have been gathered in the UMD TP53 database (http://p53.fr). Analyses of these mutations have been invaluable for bettering our knowledge on the structure/function relationships within the TP53 protein and the high degree of heterogeneity of the various TP53 mutants in human cancer. In this review, we discuss how with the release of the sequences of thousands of tumor [...]

Menée in vitro, cette étude met en évidence des mécanismes liés à la présence de la mutation R882H du gène DNMT3A, codant une méthyltransférase, dans les génomes de cellules de leucémie myéloïde aiguë

The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers

Russler-Germain, David A ; Spencer, David H ; Young, Margaret A ; Lamprecht, Tamara L ; Miller, Christopher A ; Fulton, Robert ; Meyer, Matthew R ; Erdmann-Gilmore, Petra ; Townsend, R.  Reid ; Wilson, Richard K ; Ley, Timothy J

Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in <30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by <80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of [...]

Menée sur plusieurs cohortes de patients pédiatriques atteints d'une leucémie aiguë lymphoblastique avec amplification de grandes régions du chromosome 21, cette étude met en évidence divers mécanismes susceptibles d'induire de telles anomalies génomiques

Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia

Li, Yilong ; Schwab, Claire ; Ryan, Sarra L. ; Papaemmanuil, Elli ; Robinson, Hazel M. ; Jacobs, Patricia ; Moorman, Anthony V. ; Dyer, Sara ; Borrow, Julian ; Griffiths, Mike ; Heerema, Nyla A. ; Carroll, Andrew J. ; Talley, Polly ; Bown, Nick ; Telford, Nick ; Ross, Fiona M. ; Gaunt, Lorraine ; McNally, Richard J. Q. ; Young, Bryan D. ; Sinclair, Paul ; Rand, Vikki ; Teixeira, Manuel R. ; Joseph, Olivia ; Robinson, Ben ; Maddison, Mark ; Dastugue, Nicole ; Vandenberghe, Peter ; Haferlach, Claudia ; Stephens, Philip J. ; Cheng, Jiqiu ; Van Loo, Peter ; Stratton, Michael R. ; Campbell, Peter J. ; Harrison, Christine J.

Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, sous le contrôle du gène p53, le gène DRAGO exerce une fonction de suppresseur de tumeurs

DRAGO (KIAA0247), a New DNA Damage–Responsive, p53-Inducible Gene That Cooperates With p53 as Oncosupprossor

Polato, Federica ; Rusconi, Paolo ; Zangrossi, Stefano ; Morelli, Federica ; Boeri, Mattia ; Musi, Alberto ; Marchini, Sergio ; Castiglioni, Vittoria ; Scanziani, Eugenio ; Torri, Valter ; Broggini, Massimo

Background : p53 influences genomic stability, apoptosis, autophagy, response to stress, and DNA damage. New p53-target genes could elucidate mechanisms through which p53 controls cell integrity and response to damage. Methods : DRAGO (drug-activated gene overexpressed, KIAA0247) was characterized by bioinformatics methods as well as by real-time polymerase chain reaction, chromatin immunoprecipitation and luciferase assays, time-lapse microscopy, and cell viability assays. Transgenic mice (94 [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en réprimant l'expression de gènes activés par Notch, le gène Ikaros exerce une fonction de suppresseur de tumeurs dans les leucémies à lymphocytes T

The Tumor Suppressor Ikaros Shapes the Repertoire of Notch Target Genes in T Cells

Geimer Le Lay, Anne-Solen ; Oravecz, Attila ; Mastio, Jerome ; Jung, Claudia ; Marchal, Patricia ; Ebel, Claudine ; Dembele, Doulaye ; Jost, Bernard ; Le Gras, Stephanie ; Thibault, Christelle ; Borggrefe, Tilman ; Kastner, Philippe ; Chan, Susan

The Notch signaling pathway is activated in many cell types, but its effects are cell type– and stage-specific. In the immune system, Notch activity is required for the differentiation of T cell progenitors, but it is reduced in more mature thymocytes, in which Notch is oncogenic. Studies based on single-gene models have suggested that the tumor suppressor protein Ikaros plays an important role in repressing the transcription of Notch target genes. We used genome-wide analyses, including [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en régulant l'activité de PI3K, le gène BRD7 exerce une fonction de suppresseur de tumeurs

BRD7, a Tumor Suppressor, Interacts with p85± and Regulates PI3K Activity

Chiu, Yu-Hsin ; Lee, Jennifer Y ; Cantley, Lewis C

Phosphoinositide 3-kinase (PI3K) activity is important for regulating cell growth, survival, and motility. We report here the identification of bromodomain-containing protein 7 (BRD7) as a p85

Menée in vitro, in vivo et sur 173 échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence des mécanismes par lesquels un gène identifié précédemment dans des études d'association sur le génome entier, CLPTM1L, favorise la croissance tumorale

CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells

Jia, Jinping ; Bosley, Allen D. ; Thompson, Abbey ; Hoskins, Jason W ; Cheuk, Adam ; Collins, Irene ; Parikh, Hemang ; Xiao, Zhen ; Ylaya, Kris ; Dzyadyk, Marta ; Cozen, Wendy ; Hernandez, Brenda Y. ; Lynch, Charles F. ; Loncarek, Jadranka ; Altekruse, Sean F. ; Zhang, Lizhi ; Westlake, Christopher J. ; Factor, Valentina M. ; Thorgeirsson, Snorri ; Bamlet, William R ; Hewitt, Stephen M. ; Petersen, Gloria M. ; Andresson, Thorkell ; Amundadottir, Laufey T.

Genome wide association studies (GWAS) of ten different cancers have identified pleiotropic cancer predisposition loci across a region of chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic cancer have mapped to the CLPTM1L gene, thus prompting an investigation of the function of CLPTM1L in the pancreas. Immunofluorescence analysis indicated that CLPTM1L localized to the endoplasmic reticulum (ER) where it is likely embedded in the [...]

A partir de 13 bases de données d'expression de gènes portant sur un total de 2 026 échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome du poumon, cette méta-analyse identifie une surexpression fréquente du gène PTK7

A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma

Chen, Ron ; Khatri, Purvesh ; Mazur, Pawel K. ; Polin, Melanie ; Zheng, Yanyan ; Vaka, Dedeepya ; Hoang, Chuong D. ; Shrager, Joseph ; Xu, Yue ; Vicent, Silvestre ; Butte, Atul ; Sweet-Cordero, E. Alejandro

Lung cancer remains the most common cause of cancer-related death worldwide and it continues to lack effective treatment. The increasingly large and diverse public databases of lung cancer gene expression constitute a rich source of candidate oncogenic drivers and therapeutic targets. To define novel targets for lung adenocarcinoma (ADC), we conducted a large scale meta-analysis of genes specifically overexpressed in ADC. We identified an eleven-gene signature that was overexpressed [...]

Menée à l'aide de modèles murins et sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer du côlon, cette étude met en évidence des mécanismes par lesquels le gène RIP140 joue un rôle de suppresseur de tumeurs

RIP140 increases APC expression and controls intestinal homeostasis and tumorigenesis

Lapierre, Marion ; Bonnet, Sandrine ; Bascoul-Mollevi, Caroline ; Ait-Arsa, Imade ; Jalaguier, St ; xE, ; phan, ; Del Rio, Maguy ; Plateroti, Michela ; Roepman, Paul ; Ychou, Marc ; Pannequin, Julie ; Hollande, Fr ; ric, ; Parker, Malcolm ; Cavailles, Vincent

Deregulation of the Wnt/APC/β-catenin signaling pathway is an important consequence of tumor suppressor APC dysfunction. Genetic and molecular data have established that disruption of this pathway contributes to the development of colorectal cancer. Here, we demonstrate that the transcriptional coregulator RIP140 regulates intestinal homeostasis and tumorigenesis. Using Rip140-null mice and mice overexpressing human RIP140, we found that RIP140 inhibited intestinal epithelial cell proliferation [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes d'inhibition de la transcription du gène suppresseur de tumeurs EPHB3 dans le cancer colorectal

Silencing of the EPHB3 tumor-suppressor gene in human colorectal cancer through decommissioning of a transcriptional enhancer

Jägle, Sabine ; Rönsch, Kerstin ; Timme, Sylvia ; Andrlová, Hana ; Bertrand, Miriam ; Jäger, Marcel ; Proske, Amelie ; Schrempp, Monika ; Yousaf, Afsheen ; Michoel, Tom ; Zeiser, Robert ; Werner, Martin ; Lassmann, Silke ; Hecht, Andreas

The protein tyrosine kinase Ephrin type-B receptor 3 (EPHB3) counteracts tumor-cell dissemination by regulating intercellular adhesion and repulsion and acts as tumor/invasion suppressor in colorectal cancer. This protective mechanism frequently collapses at the adenoma–carcinoma transition due to EPHB3 transcriptional silencing. Here, we identify a transcriptional enhancer at the EPHB3 gene that integrates input from the intestinal stem-cell regulator achaete-scute family basic [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une surexpression du gène SPOP, qui code une ubiquitine ligase, favorise le développement d'un carcinome rénal à cellules claires

SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer

Li, Guoqiang ; Ci, Weimin ; Karmakar, Subhradip ; Chen, Ke ; Dhar, Ruby ; Fan, Zhixiang ; Guo, Zhongqiang ; Zhang, Jing ; Ke, Yuwen ; Wang, Lu ; Zhuang, Min ; Hu, Shengdi ; Li, Xuesong ; Zhou, Liqun ; Li, Xianghong ; Calabrese, Matthew F ; Watson, Edmond R ; Prasad, Sandip M ; Rinker-Schaeffer, Carrie ; Eggener, Scott E ; Stricker, Thomas ; Tian, Yong ; Schulman, Brenda A ; Liu, Jiang ; White, Kevin P

Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC). Furthermore, hypoxia results in cytoplasmic accumulation of SPOP, which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation [...]

Menée sur des lignées cellulaires, à l'aide de xénogreffes et d'échantillons tumoraux prélevés sur 383 patientes atteintes d'un cancer du sein triplement négatif, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation HIF1

XBP1 promotes triple-negative breast cancer by controlling the HIF1

Chen, Xi ; Iliopoulos, Dimitrios ; Zhang, Qing ; Tang, Qianzi ; Greenblatt, Matthew B. ; Hatziapostolou, Maria ; Lim, Elgene ; Tam, Wai Leong ; Ni, Min ; Chen, Yiwen ; Mai, Junhua ; Shen, Haifa ; Hu, Dorothy Z. ; Adoro, Stanley ; Hu, Bella ; Song, Minkyung ; Tan, Chen ; Landis, Melissa D. ; Ferrari, Mauro ; Shin, Sandra J. ; Brown, Myles ; Chang, Jenny C. ; Liu, X. Shirley ; Glimcher, Laurie H.

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. [...]

Cet article passe en revue les travaux récents sur le rôle des mutations du gène p53 dans le processus métastatique

Contribution of p53 to Metastasis

Powell, Emily ; Piwnica-Worms, David ; Piwnica-Worms, Helen

The tumor suppressor p53 is lost or mutated in about half of all human cancers, and in those tumors in which it is wild-type, mechanisms exist to prevent its activation. p53 loss not only prevents incipient tumor cells from undergoing oncogene-induced senescence and apoptosis, but also perturbs cell-cycle checkpoints. This enables p53-deficient tumor cells with DNA damage to continue cycling, creating a permissive environment for the acquisition of additional mutations. Theoretically, this [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en interaction avec le micro-ARN-199a et le facteur HIF, le gène DNM2 régule le processus métastatique d'un cancer de l'ovaire

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Joshi, Hemant P. ; Subramanian, Indira V. ; Schnettler, Erica K. ; Ghosh, Goutam ; Rupaimoole, Rajesha ; Evans, Colleen ; Saluja, Manju ; Jing, Yawu ; Cristina, Ivan ; Roy, Sabita ; Zeng, Yan ; Shah, Vijay H. ; Sood, Anil K. ; Ramakrishnan, Sundaram

Hypoxia-driven changes in the tumor microenvironment facilitate cancer metastasis. In the present study, we investigated the regulatory cross talk between endocytic pathway, hypoxia, and tumor metastasis. Dynamin 2 (DNM2), a GTPase, is a critical mediator of endocytosis. Hypoxia decreased the levels of DNM2. DNM2 promoter has multiple hypoxia-inducible factor (HIF)-binding sites and genetic deletion of them relieved hypoxia-induced transcriptional suppression. Interestingly, DNM2 reciprocally [...]

Menée sur des échantillons tumoraux prélevés sur 3 cohortes de patients atteints d'un cancer colorectal, cette étude met en évidence des anomalies d'expression de cytokines associées à la progression tumorale

Functional Network Pipeline Reveals Genetic Determinants Associated with in Situ Lymphocyte Proliferation and Survival of Cancer Patients

Mlecnik, Bernhard ; Bindea, Gabriela ; Angell, Helen K. ; Sasso, Maria Stella ; Obenauf, Anna C. ; Fredriksen, Tessa ; Lafontaine, Lucie ; Bilocq, Amelie M. ; Kirilovsky, Amos ; Tosolini, Marie ; Waldner, Maximilian ; Berger, Anne ; Fridman, Wolf Herman ; Rafii, Arash ; Valge-Archer, Viia ; Pagès, Franck ; Speicher, Michael R. ; Galon, Jérôme

The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with [...]

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, puis sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène Sox2, le micro-ARN miR-200c favorise le processus métastatique

Regulation of colorectal carcinoma stemness, growth and metastasis by a miR-200c-Sox2 negative feedback loop mechanism

Li, Xue Nong ; Lu, Yan xia ; Li, Yuan ; Xue, Xiao lei ; Zhou, Min ; Liu, Yan ; Zhang, Chao ; Li, Jing ping ; Zheng, Lin ; Hong, Min

Purpose:To elucidate a novel mechanism of miR-200c in the regulation of stemness, growth and metastasis in colorectal carcinoma (CRC). Experimental Design:Quantitative reverse transcription-PCR was used to quantify miR-200c expression in CRC cell lines and tissues. A luciferase assay was adopted for the target evaluation. The functional effects of miR-200c in CRC cells were assessed either by its forced or inhibited expression using lentiviruses. Results:MiR-200c was statistically lower in CRC [...]