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![Control of mammary epithelial differentiation by the extracellular matrix için kapak resmi Control of mammary epithelial differentiation by the extracellular matrix için kapak resmi](/client/assets/d79c3e4af2b6d196/ctx/images/no_image.png)
Control of mammary epithelial differentiation by the extracellular matrix
Başlık:
Control of mammary epithelial differentiation by the extracellular matrix
Yazar:
Watkin, Harriet Lucy, author.
ISBN:
9780438085381
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (261 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Signals regulating cell proliferation, differentiation and survival originate from a variety of sources including the extracellular matrix and soluble ligands. One stimulus alone does not control cell fate but different signals converge and crosstalk within the cell. In the mammary gland, lactogenic hormones and growth factors are not the sole mediators of epithelial differentiation and cell survival, but act in concert with signals provided by a laminin-rich basement membrane. Indeed, a specific domain within laminin, the E3 region, is essential for lactogenic hormone-dependent beta-casein gene expression. The lactogenic hormone prolactin is an essential modulator of mammary gland development and differentiation. Prolactin triggers a tyrosine phosphorylation cascade within the cell, mediated via prolactin receptor and the associated tyrosine kinase Jak2. This leads to the recruitment of Stat5, which subsequently becomes phosphorylated itself enabling it to dimerise and translocate to the nucleus. Stat5 dimers bind to specific regulatory elements within the promoters of milk protein genes leading to the activation of transcription of proteins such as beta-casein. Experiments have shown that a laminin-rich basement membrane is mandatory for the prolactin induced DNA binding activity of Stat5. In fact, a laminin-rich basement membrane is required for the prolactin receptor to become activated by its ligand. I now suggest a mechanism for this whereby the extracellular matrix regulates the expression levels of prolactin receptor itself. To further elucidate the molecular mechanisms underlying the crosstalk between signals for the extracellular matrix and soluble factors, I have developed a method of gene transfer to primary mammary epithelial cells using adenovirus. The novel infection procedure I have employed allows the expression of heterologous proteins with over 95% efficiency in cells cultured both in monolayer and in multicellular clusters in a three-dimensional matrix. This technique paves the way for modem molecular analysis of signal transduction and cell phenotype in primary mammary epithelial cells that was previously not possible. Integrins link the extracellular matrix to both the cell's cytoskeleton and signalling pathways and have been shown to regulate cellular responses to soluble ligands. In the case of the mammary gland beta1, integrin is an essential mediator of the signals from the extracellular matrix required for epithelial differentiation and survival. Integrin activation upon binding to extracellular matrix ligands induces the recruitment of a structural and signalling proteins resulting in the formation of focal adhesions. Focal adhesion kinase (FAK) is one such protein and it plays a critical role in integrin-mediated signalling. I have investigated the role of FAK in mammary epithelial differentiation using a dominant-negative approach. Adenovirus-mediated gene transfer allowed successful delivery of a dominant-negative FAK construct to primary mammary epithelial cells. This was monitored by displacement of endogenous FAK from focal contacts and inhibition of FAK tyrosine phosphorylation. However, expression of dominant-negative FAK in primary mammary epithelial cells did not perturb beta-casein gene expression. This indicates that FAK is not an essential mediator of mammary epithelial differentiation.
Notlar:
School code: 1543
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(686956.1) | 686956-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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