Regulation of HBP1 via the AKT/FOXO pathway and impact on cell proliferation
(2018)
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- Abstract
- Phosphatidylinositol-3-kinase (PI3K) and AKT control key signal transduction pathways that are activated by growth factor receptors, leading to cell proliferation, survival and growth. In this thesis, we identified a novel target of these pathways, the HMG-box protein 1 (HBP1), a ubiquitous transcriptional regulator that promotes cell cycle arrest and premature senescence. In line with its functional roles, HBP1 has been proposed to act as a tumor suppressor. In our first study, we showed that activation of the PI3K/AKT pathway by growth factors repressed HBP1 expression at the transcriptional level by inhibiting forkhead-box O (FOXO) binding to the HBP1 gene promoter. This regulation was observed in human fibroblasts as well as in cancer cell lines. In addition, we noticed that HBP1 and FOXO1 expression were both down-regulated in breast cancer samples compared to normal samples. In our second study, we identified HBP1 as a novel substrate of AKT. We found that AKT phosphorylated HBP1 at three conserved sites: Ser380, Thr484 and Ser509. HBP1 phosphorylation was induced by growth factors that activate the PI3K/AKT pathway and was blocked by AKT inhibition or knock-down. In addition, we observed that HBP1 transcriptional activity was modified by mutating its phosphorylation sites. HBP1 phosphorylation by AKT reduced its transcriptional activity. Using small-hairpin RNA (shRNA), we found that HBP1 knock-down increased human glioblastoma cell proliferation. Conversely, HBP1 overexpression reduced glioma cell growth and transformation. Finally, we showed that the effect of HBP1 on glioma cell growth was altered by its phosphorylation, indicating that HBP1 might be down-regulated by the PI3K/AKT pathway in gliomas. To conclude, our results showed that the PI3K/AKT pathway regulates HBP1 downstream of growth factors by two parallel mechanisms, at the post-translational and transcriptional levels, preventing its inhibitory effect on cell proliferation.
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Bollaert, E. (2018). Regulation of HBP1 via the AKT/FOXO pathway and impact on cell proliferation. https://hdl.handle.net/2078.5/93195