Cell cycle lab
Pierre Roger pioneered the study of proliferation and differentiation of thyroid cells by defining model systems of primary cultures in chemically defined medium (without serum). Using these systems, he demonstrated and characterized the unique coexistence in these cells of two distinct proliferation modes, activated by TSH (only via cAMP elevation and PKA activation) or by several growth factors (via Ras, MAP kinase and PI3kinase cascades). The cAMP pathway simultaneously stimulates proliferation and differentiation expression in thyrocytes, and is involved in goitrigenesis and generation of hyperfunctional adenomas, whereas the growth factor pathways induce dedifferentiation and are involved in thyroid carcinomas. In thyroid primary cultures, the positive cell cycle regulation by cAMP is unique as it targets the assembly and then the activation of complexes formed by preexisting cyclin D3 and cyclin-dependent kinase (CDK) 4, without involving most intermediaries of classical mitogenic signaling cascades.
The present research interests of our group include the cellular and molecular features of cell cycle regulation in this model system and several others (investigation of cyclins, CDKs, their inhibitors, the interactions between these different proteins and their posttranslational modifications). Using two-dimensional electrophoresis to separate the phosphorylated forms of these proteins within their various complexes LINK to “Revisiting post-translational regulation of CDKs”, we identified the activating phosphorylation of CDK4 as a direct crucial target for cell cycle regulation in various cell systems LINK to “RB & CDK4 in cell cycle and cancer”.
Using various molecular, cellular, proteomic and bioinformatic approaches, we are currently (i) exploring the mechanisms of this critical CDK4 regulation that determines the inactivation of the central oncosuppressor protein pRb and the cell cycle decision in normal and cancerous cells; (ii) developing novel tools to predict whether cancer patients will benefit or not of treatments with the new CDK4 inhibitory drugs that are now approved for treatment of advanced ER+ breast cancers.