Our laboratory is interested in molecular circuitries implicated in cellular senescence and stem cell activities, and how deregulation of these biological processes affects organismal aging and tumorigenesis. One of our main research topic is the characterization of new regulatory mechanisms of the p53 pathway. Functional inactivation of the p53 pathway occurs in most, if not all, human tumors, and deregulation of p53 activities is also associated with premature aging phenotypes. More specifically, we are investigating the roles of several important components of this pathway, including those mediated by the multifunctional protein E4F1 and the MDM2 oncoprotein. Over the past years, we unraveled previously unknown metabolic functions of these p53 regulators, connecting this tumor suppressor pathway to obesity, diabetes, muscular endurance and stem cell function. Consistent with our findings, deregulation of these metabolic networks has been associated with several human metabolic syndromes associated with mitochondrial deficiencies, including the Leigh Syndrome. To further explore these metabolic networks, we use several complementary approaches such as whole genome ChIP-seq, metabolomics, stable isotope tracing approaches, and computational modeling. We also generated several genetically engineered mouse models to study the in vivo relevance of E4F1- and MDM2- associated metabolic functions during normal development, aging and tumorigenesis.
Our projects aim at further characterizing the role of these metabolic networks in human patho-physiology. We expect that a better understanding of these networks will have potential applications in regenerative medecine and will lead to the development of innovative anti-cancer therapies.
Lacroix M, Rodier G, Kirsh O, Houles T, Delpech H, Seyran B, Gayte L, Casas F, Pessemesse L, Heuillet M, Bellvert F, Portais JC, Berthet C, Bernex F, Brivet M, Boutron A, Le Cam L, Sardet C. E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity. Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):10998-1003
Goguet-Rubio P, Seyran B, Gayte L, Bernex F, Sutter A, Delpech H, Linares LK, Riscal R, Repond C, Rodier G, Kirsh O, Touhami J, Noel J, Vincent C, Pirot N, Pavlovic G, Herault Y, Sitbon M, Pellerin L, Sardet C, Lacroix M, Le Cam L. E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis. Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):11004-9
Sardet C., Lacroix M. and Le Cam L. (2016) E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis. Proc Natl Acad Sci U S A. 113(39):11004-9
Riscal R, Schrepfer E, Arena G, Cissé MY, Bellvert F, Heuillet M, Rambow F, Bonneil E, Sabourdy F, Vincent C, Ait-Arsa I, Levade T, Thibaut P, Marine JC, Portais JC, Sarry JE, Le Cam L, Linares LK. Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53. Molecular-Cell, fulltext, S 1097-2765(16)30109-5
Rodier G, Kirsh O, Baraibar M, Houlès T, Lacroix M, Delpech H, Hatchi E, Arnould S, Severac D, Dubois E, Caramel J, Julien E, Friguet B, Le Cam L, Sardet C. The transcription factor E4F1 coordinates CHK1-dependent checkpoint and mitochondrial functions. Cell Rep. 2015 Apr 14;11(2):220-33.
Lacroix M, Caramel J, Goguet-Rubio P, Linares LK, Estrach S, Hatchi E, Rodier G, Lledo G, de Bettignies C, Thépot A, Deraison C, Chébli K, Hovnanian A, Hainaut P, Dubus P, Sardet C, Le Cam L. Transcription factor E4F1 is essential for epidermal stem cell maintenance and skin homeostasis. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21076-81
Le Cam L, Linares LK, Paul C, Julien E, Lacroix M, Hatchi E, Triboulet R, Bossis G, Shmueli A, Rodriguez MS, Coux O, Sardet C. (2006). E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell. Nov17;127(4): 775- 88.