E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis

E4F1 deficiency results in oxidative stress–mediated cell death of leukemic cells

Deletion of E4F1 inflicts mitochondrial damage and oxidative stress on murine and human myeloid leukemia cells but not healthy macrophages

Rôle du suppresseur de tumeurs p53 dans le contrôle du métabolisme

International audienceThe p53 tumor suppressor is an essential downstream effector of various cellular stress response pathways that is functionally inactivated in most, if not all, tumors. Since its discovery more than 30 years ago, its role in the control of cell proliferation, senescence and cell survival has been widely described. However, growing evidences from several laboratories indicate that p53 has important transcriptional and non-transcriptional functions in the control of metabolism, including the regulation of glycolysis, glutaminolysis or mitochondrial respiration. Originally identified using in vitro cellular models, this previously underestimated role of p53 has been confirmed in vivo in various genetically engineered mouse models. These recent data suggest that p53 functions in various metabolic pathways significantly contribute to its role in adult tissue homeostasis, aging as well as tumor suppression.Le suppresseur de tumeurs p53 est un médiateur essentiel des voies de réponse cellulaire à des stress de nature très variée qui est inactivé dans la majorité des tumeurs. Au-delà de ses fonctions connues dans le contrôle de la prolifération, de la sénescence ou de la mort cellulaire, des résultats récents de différents laboratoires indiquent que p53 joue de multiples rôles dans le contrôle du métabolisme énergétique, et qu’il est lui même régulé par de nombreux changements métaboliques. Il est vraisemblable que ces actions de p53, encore mal connues, jouent un rôle important, à la fois pour les fonctions de suppresseur de tumeurs de cette protéine, mais également dans l’homéostasie tissulaire, ainsi qu’au cours du vieillissement

Chromatin-bound MDM2, a new player in metabolism

International audienceThe oncoprotein MDM2 is recognized as a major negative regulator of the p53 tumor suppressor but growing evidence indicates that its oncogenic activities extend beyond p53. We show that MDM2 is recruited to chromatin independently of p53 to regulate a transcriptional program implicated in amino acid metabolism and redox homeostasis

[The Yin and the Yang of senescence: is it possible to age without developing cancer?].

International audienc

Rôle du suppresseur de tumeurs p53 dans le contrôle du métabolisme

Le suppresseur de tumeurs p53 est un médiateur essentiel des voies de réponse cellulaire à des stress de nature très variée qui est inactivé dans la majorité des tumeurs. Au-delà de ses fonctions connues dans le contrôle de la prolifération, de la sénescence ou de la mort cellulaire, des résultats récents de différents laboratoires indiquent que p53 joue de multiples rôles dans le contrôle du métabolisme énergétique, et qu’il est lui même régulé par de nombreux changements métaboliques. Il est vraisemblable que ces actions de p53, encore mal connues, jouent un rôle important, à la fois pour les fonctions de suppresseur de tumeurs de cette protéine, mais également dans l’homéostasie tissulaire, ainsi qu’au cours du vieillissement

Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells

The E6 oncoprotein of human papillomaviruses (HPVs) that are associated with cervical cancer utilizes the cellular ubiquitin–protein ligase E6-AP to target the tumor suppressor p53 for degradation. In normal cells (i.e., in the absence of E6), p53 is also a target of the ubiquitin–proteasome pathway. Under these conditions, however, p53 degradation is mediated by Mdm2 rather than by E6-AP. Here we show in a mutational analysis that, surprisingly, the structural requirements of p53 to serve as a proteolytic substrate differ between E6 proteins derived from different HPV types and, as expected, between Mdm2 and E6 proteins in vitro and in vivo. Stable expression of such mutants in HPV-negative and HPV-positive cell lines demonstrates that in HPV-positive cancer cells, the E6-dependent pathway of p53 degradation is not only active but, moreover, is required for degradation of p53, whereas the Mdm2-dependent pathway is inactive. Because the p53 pathway was reported to be functional in HPV-positive cancer cells, this finding indicates clearly that the ability of the E6 oncoprotein to target p53 for degradation is required for the growth of HPV-positive cancer cells

Method to determine bones' relative displacement using a CT scan: application to the scaphoid and lunate bones

International audienceno abstrac

Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer

International audienceBACKGROUND:The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells.SCOPE OF REVIEW:We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases.MAJOR CONCLUSIONS:p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression

Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation

Acetylation is a prominent post-translational modification of nucleosomal histone N-terminal tails, which regulates chromatin accessibility. Accordingly, histone acetyltransferases (HATs) play major roles in processes such as transcription. Here, we show that the HAT Tip60, which is involved in DNA repair and apoptosis following γ irradiation, is subjected to proteasome-dependent proteolysis. Furthermore, we provide evidence that Mdm2, the ubiquitin ligase of the p53 tumour suppressor, interacts physically with Tip60 and induces its ubiquitylation and proteasome-dependent degradation. Moreover, a ubiquitin ligase-defective mutant of Mdm2 had no effect on Tip60 stability. Our results indicate that Mdm2 targets both p53 and Tip60, suggesting that these two proteins could be co-regulated with respect to protein stability. Consistent with this hypothesis, Tip60 levels increased significantly upon UV irradiation of Jurkat cells. Collectively, our results suggest that degradation of Tip60 could be part of the mechanism leading to cell transformation by Mdm2