Conferences
2015
Conférence GIRC
Grenoble Institute for Cancer Research
.
Tuesday 15 Septembre
Claude Sardet
Institut de Recherche en Cancérologie, Montpellier
IAB Conference room 11 am
Coordinated Controls of checkpoints and
metabolism by E4F1: cancer vulnerabilities?
E4F1 was initially identified as a cellular transcription factor targeted by the adenoviral E1A
oncoprotein. Its cellular activities remain poorly understood but are clearly essential for early
embryogenesis, cell proliferation, differentiation or survival of various cell types. E4F1-/- mouse
embryos die at the peri-implantation stage and exhibit mitotic progression defects, chromosomal
missegregation and increased apoptosis. E4F1 is involved in several essential oncogenic pathways. It
is targeted by viral oncoproteins and physically interacts with several bona fide cellular tumor
suppressors and oncoproteins (RASSF1A, pRB, p14ARF, p53, Bmi1), suggesting that it might itself
be involved in tumorigenesis. We also found that E4F1 is a multi-fonctional protein with an intrinsic
transcriptional activity and an atypical ubiquitin E3-ligase activity that targets p53: E4F1-mediated
ubiquitylation of p53, instead of promoting p53 proteolysis, modulates p53 effector functions involved
in alternative cell fates, growth arrest or apoptosis (Le Cam et al., Cell 2006). More recently, using
conditional E4F1 KO mouse models with or without a functional p53 pathway, we observed that
E4F1 also controls a p53-independent program essential for the survival of cancer cells and stem cells
(Lacroix et al., PNAS 2010, Hatchi et al, J. Exp. Med. 2011). Acute E4F1 depletion in fully
transformed Mefs or in leukemic cells results in p53-independent massive cell death associated with
mitochondrial disfunctions, over-production of mitochondrial ROS an DNA damage. E4F1 target
genes (110) have been identified using genome wide ChiP-seq analyses and expression profiling of
E4F1 KO cells and animals (Rodier et al. Cell Reports 2015, Houlès et al Genomics Data 2015). E4F1
controls a small but essential set of genes important for mitochondrial homeostasis, energy metabolism
(including a novel "PDH regulon"), nucleotide synthesis AND stress/checkpoint regulators, suggesting
it coordinates metabolism and proliferation/survival. This E4F1 program identifies novel and
unexpected synthetic lethalities between metabolic pathways and cell cycle/stress checkpoints that
could be essential for cancer cells survival. We will present an example of such E4F1 KO-driven
synthetic lethal strategy that kills efficiently transformed cells.
Invited by Pierre Hainaut
Grenoble Institut Recherche Cancer : Institut Albert Bonniot, Institut de Recherches en
Technologies et Sciences pour le
Vivant, Institut de Biologie Structurale, Grenoble Institut Neurosciences
Rond Point de La Chantourne, 38700 La Tronche (tram line B, stop: Grand Sablon)
The seminar is followed by discussions and exchanges with the speaker and a sandwich buffet is offered.
http://www-iab.ujf-grenoble.fr