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International audience; Treating metastatic cancers is an ongoing challenge in oncology. A recent paper by Gomes and colleagues proposes histone H3 variant dynamics as major regulator of cell fate transition during metastasis and suggests histone chaperones as therapeutic targets for invasive carcinoma.; Le traitement des cancers métastatiques est un défi permanent en oncologie. Un article récent de Gomes et ses collègues propose la dynamique du variant de l'histone H3 comme régulateur majeur de la transition du destin cellulaire pendant la métastase et suggère les chaperons d'histones comme cibles thérapeutiques pour les carcinomes invasifs.

In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A. We delineate functional CDE/CHR motifs within the Hjurp and Cenpa promoters and demonstrate their roles in p53-mediated repression. To assess the importance of HJURP up-regulation in transformed murine and human cells, we used a CRISPR/Cas9 approach. Remarkably, depletion of HJURP leads to distinct outcomes depending on their p53 status. Functional p53 elicits a cell cycle arrest response, whereas, in p53-null transformed cells, the absence of arrest enables the loss of HJURP to induce severe aneuploidy and, ultimately, apoptotic cell death. We thus tested the impact of HJURP depletion in pre-established allograft tumors in mice and revealed a major block of tumor progression in vivo. We discuss a model in which an “epigenetic addiction” to the HJURP chaperone represents an Achilles’ heel in p53-deficient transformed cells.

International audience; Mutations in p53, although frequent in human cancers , have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53 D31 , a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53 D31/D31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Hetero-zygous p53 +/D31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53 D31/D31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.

Mdm4, a protein related to the ubiquitin-ligase Mdm2, is an essential inhibitor of tumor suppressor protein p53. In both human and mouse cells, the Mdm4 gene encodes two major transcripts: one encodes the full-length oncoprotein (designated below as Mdm4-FL), whereas the other, resulting from a variant splicing that skips exon 6, encodes the shorter isoform Mdm4-S. Importantly, increased Mdm4-S mRNA levels were observed in several human cancers, and correlated with poor survival. However, the role of Mdm4-S in cancer progression remains controversial, because the Mdm4-S protein appeared to be a potent p53 inhibitor when overexpressed, but the splice variant also leads to a decrease in Mdm4-FL expression. To unambiguously determine the physiological impact of the Mdm4-S splice variant, we generated a mouse model with a targeted deletion of the Mdm4 exon 6, thereby creating an obligatory exon skipping. The mutant allele (Mdm4(ΔE6)) prevented the expression of Mdm4-FL, but also led to increased Mdm4-S mRNA levels. Mice homozygous for this allele died during embryonic development, but were rescued by a concomitant p53 deficiency. Furthermore in a hypomorphic p53(ΔP/ΔP) context, the Mdm4(ΔE6) allele led to p53 activation and delayed the growth of oncogene-induced tumors. We next determined the effect of Mdm4(+/ΔE6) heterozygosity in a hypermorphic p53(+/Δ31) genetic background, recently shown to be extremely sensitive to Mdm4 activity. Mdm4(+/ΔE6) p53(+/Δ31) pups were born, but suffered from aplastic anemia and died before weaning, again indicating an increased p53 activity. Our results demonstrate that the main effect of a skipping of Mdm4 exon 6 is not the synthesis of the Mdm4-S protein, but rather a decrease in Mdm4-FL expression. These and other data suggest that increased Mdm4-S mRNA levels might correlate with more aggressive cancers without encoding significant amounts of a potential oncoprotein. Hypotheses that may account for this apparent paradox are discussed.

International audience; The clinical importance of tumor suppressor p53 makes it one of the most studied transcription factors. A comparison of mammalian p53 transcriptional repertoires may help identify fundamental principles in genome evolution and better understand cancer processes. Here we summarize mechanisms underlying the divergence of mammalian p53 transcriptional repertoires, with an emphasis on the rapid evolution of fuzzy tandem repeats containing p53 response elements.

International audience; Although our knowledge of the biology of brain tumors has increased tremendously over the past decade, progress in treatment of these deadly diseases remains modest. Developing in vivo models that faithfully mirror human diseases is essential for the validation of new therapeutic approaches. Genetically engineered mouse models (GEMMs) provide elaborate temporally and genetically controlled systems to investigate the cellular origins of brain tumors and gene function in tumorigenesis. Furthermore, they can prove to be valuable tools for testing targeted therapies. In this review, we discuss GEMMs of brain tumors, focusing on gliomas and medulloblastomas. We describe how they provide critical insights into the molecular and cellular events involved in the initiation and maintenance of brain tumors, and illustrate their use in preclinical drug testing.

Inactivation de p53 dans les cancers p53 est l’un des facteurs de transcription les plus etudies du fait de son importance clinique. En effet, le gene TP53 est mute dans plus de la moitie des cancers sporadiques, et la plupart des autres cancers surexpriment Mdm2 ou Mdm4, les principaux regulateurs negatifs de p53. De plus, les mutations germinales de TP53 causent le syndrome Li-Fraumeni de predisposition au cancer [1]. En reponse a divers stress cellulaires, notamment les cassures d’ADN et les signaux oncogeniques, la proteine p53 est stabilisee et activee. Elle induit alors la transcription de multiples genes impliques dans l’arret du cycle cellulaire, la senescence, l’apoptose et diverses regulations metaboliques, qui contribuent a sa fonction de suppresseur de tumeur. Ainsi, p53 empeche la proliferation de cellules dont le genome est altere, ce qui lui a valu le surnom de « gardien du genome » [2]. La plupart des mutations du gene TP53 identifiees dans les cancers sont des mutations faux-sens ; elles affectent une region centrale de la proteine qui correspond au domaine de liaison a l’ADN qui reconnait les promoteurs des genes cibles de p53. Ces mutations sont essentiellement inactivatrices : elles reduisent ou abolissent la capacite de la proteine mutante a lier l’ADN, et donc a reguler ses cibles transcriptionnelles.

International audience; No abstract available

p53 was discovered in 1979 in SV40-transformed cells as a cellular protein that forms a complex with the large T antigen (DeLeo et al., 1979; Kress et al., 1979; Lane and Crawford, 1979; Linzer and Levine, 1979). It was originally identified as an oncoprotein, but was shown to be a tumor suppressor ten years later by both in vitro experiments and human tumor sample studies (Baker et al., 1989; Finlay et al., 1989; Hinds et al., 1989; Nigro et al., 1989).

International audience; No abstract available