Limna - Lausanne Integrative Metabolism Nutrition Alliance

Professor
Lluis Fajas Coll

Center for Integrative Genomics – UNIL

Cell cycle regulators control metabolism in normal and pathological conditions such as obesity, diabetes and cancer

We focus our work on the elucidation of the mechanisms implicated in the metabolic response of the cells to particular stimuli and how this response participates in the maintenance of a transformed phenotype. The response of the cell to external stimuli depends on the cellular context and the cellular need at a particular moment. A summary of our hypothesis and findings is depicted in the figure.

We have enough evidence to propose that cell cycle regulators, in addition to trigger proliferation of the cells, they participate in the adapted switch required to the metabolic adaptation required to the particular response of the cell, such as proliferation, development, regeneration, survival, or specific function. Currently, proteins such as cyclins, cdk, or E2Fs are being studied in the context of proliferation, cell cycle regulation and cancer. However, we have already demonstrated that these factors play crucial roles in the control of metabolism. Our studies contribute to the understanding of the metabolic changes taking place during different physio-pathological conditions, such as obesity, diabetes, or cancer. Our work is based in the phenotype of mice models deficient of specific cell cycle regulators.


In particular the following projects are being developed in the lab:

1. Participation of pRB-cdk4-E2F1 in lipogenesis, glycolysis and oxidative metabolism.

We want to prove that this pathway plays a central role in these pathways. We identify direct targets of this pathway using ChIP-seq analyses. Our data indicate that FAS, ELOVL6, SCD1 and Hexokinase are E2F1 target genes, which we are validating with E2F1-/-, cdk4-/- mice. We generate adipose tissue- (for lipids) and liver-specific (for energy metabolism) conditional knockouts of E2F1-/- and cdk4-/- in mice. The metabolic phenotype of these mice will be extensively characterized. This includes, but is not limited to glucose homeostasis studies, lipids metabolism, and energy homeostasis analysis. Finally, we want to identify potential novel cdk4 targets involved in metabolism.

2. Elucidation of the molecular mechanisms underlying the differential metabolic versus proliferative E2F1-mediated response of the cells.

We want to understand how E2F1 directs the cellular response either towards a metabolic or a proliferative fate in a coordinated manner. We are using different systems in which both metabolic and proliferative pathways need to be coordinated. This is the case for tissue-regeneration experiments, such as muscle-, liver- and pancreas regeneration. Partial resection of these tissues results in a proliferative burst in order to regenerate the tissue. Interestingly, metabolic pathways are at this stage, silenced. We will define particular conditions and perform ChIP-seq analysis, coupled to gene expression data. This will differentially identify a metabolic class of E2F1-target genes, with a distinct regulatory pathway.

3. Oncogenic stimuli facilitate a metabolic switch in order to transform a normal into cancerous cell.

We aim to prove that cdk4 is a direct regulator of glycolysis and de novo fatty acid synthesis and modulates oxidative pathways in response to oncogenic transformation of the cell. We prove that cdk4 is activated by IGF signaling and, on its turn, is an activator of this pathway.

4. Implicating other cdks in metabolic control.

This will be the case for cdk7, cdk6, and cdk10. We already showed that cdk9 has a major role in adipose tissue differentiation. We will now generate conditional floxed cdk10-/- and cdk7-/- mice to have adipose tissue-, and liver-specific cdk9-/- mice. Fatty acid metabolism, glucose homeostasis and energy metabolism will be studied in these mice as described above.

Keywords

  • Metabolism
  • cell cycle regulators
  • oncogenic factors
  • lipogenesis
  • glycolysis
  • cancer
  • obesity
  • E2F1
  • ras
  • cdks

Contact

Prof. Lluis Fajas

Center for Integrative Genomics, CIG
UNIL Sorge
CH1015 Lausanne
Switzerland
 
Tel. +41 21 692 41 11

E-mail
Webpage

https://orcid.org/0000-0002-1283-9503