Publication

Fine modulation of stem cell niche through mTOR pathway : Effects of physical and molecular parameters regulating mTOR pathway on keratinocyte stem cells

Johannes Alexander Mosig
2008
Student project
Abstract

Epidermis is the outermost layer of the skin and is in direct contact with the external environment, requiring keratinocyte stem cells to adapt constantly. Recently, our laboratory has put forward the role of mTOR in temperature-mediated keratinocyte stem cell response (Brouard, Nanba et al., unpublished). In this work, I have demonstrated that mTOR (mammalian Target Of Rapamycin) protein levels in the epidermis are higher at 20°C than at 37°C, while active/phosphorylated mTOR (p-mTOR) is downregulated when temperature is decreased from 37°C to 20°C. To determine the relevance of different proteins in the mTOR signalling pathway, RNAi lentiviral constructs able to reduce cellular RNA levels were successfully designed. These include: mTORC1 and mTORC2 associated proteins (i.e. Raptor and Rictor respectively) which correspond to two major branches within the overall signalling pathway; EGF receptor (EGFR), which is one of the "entries" into the pathway; and hypoxia inducible factor (HIF-1α), since hypoxic conditions are a known input of mTOR. Then, I have shown that keratinocytes infected with a viral construct targeting EGFR initiate scattered colonies, composed of large flat cells, instead of circular and compact ones. Furthermore, these cells also have decreased EGFR levels, as well as decreased mTOR levels suggesting a direct correlation between these two members of the pathway. Finally, in order to quantify changes in growth rates and to track protein nuclear translocation upon temperature changes, a device is being developed in collaboration with the Laboratory of Biomedical Optics (LOB, Prof. T. Lasser). Taken together, my results demonstrate that mTOR plays a crucial role in modulating the stem cell niche in response to temperature variations. Furthermore, they provide some very effective tools to study and understand how these pathways regulate the keratinocyte stem cell niche.

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Ontological neighbourhood
Related concepts (36)
MTOR
The 'mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin', and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. mTOR links with other proteins and serves as a core component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes.
Notch signaling pathway
The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.
Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
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