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Identifier

000347035

Title

Μοριακός μηχανισμός απευαισθητοποίησης μελανοκυττάρων στην κυτταροστατική δράση του αυξητικού παράγοντα μετασχηματισμού β (Transforming Growth Factor β, TGF-β) κατά την καρκινογένεση : στόχος φαρμακολογικής παρέμβασης στη θεραπεία του μελανώματος

Author

Σταυρουλάκη, Μελανθία

Thesis advisor

Κρασαγάκης, Κωνσταντίνος

Reviewer

Τόσκα, Ανδρονίκη
Καρδάσης, Δημήτριος
Γεωργούλιας, Βασίλειος
Κουρούμαλης, Ηλίας
Κρύγκερ-Κρασαγάκη

Abstract

Carcinogenesis is likely to result from the production of autocrine growth factors, as well as from loss of response to polypeptide growth inhibitors. TGF-β inhibits the proliferation of normal cells, whereas the loss of its cytostatic action during carcinogenesis can occur either through gene mutations or absence of TGF-β receptors, or perturbation of the Smad signaling pathway. Cancer cells that have lost TGF-β responses become more aggressive. The TGF-β acts as a ligand, which assembles membrane receptor complexes that subsequently activate Smad proteins, which form transcriptional complexes that control gene expression. Smad proteins interact with various cofactors that bind to DNA, and form complexes with specific target genes. In malignant melanoma, the mechanism that leads to the repression of the antiproliferative effect of TGF-β remains largely unknown. The tumor promoting phorbol esters act mainly on protein kinase C (PKC), an enzyme that participates in melanocyte signal transduction and is involved in the process of melanocyte carcinogenesis. In the present investigation, we observed the complete abolishment of the cytostatic action of TGF-β in melanocytes and melanoma cells after exposure to 12-Otetradecanoylphorbol- 13-acetate (TPA), a tumor promoting phorbol ester. This was associated with downregulation of several PKC isoforms. Also, Smad-dependent transcriptional activity was suppressed in TPA-treated melanocytes. Using specialized PKC inhibitors and a PKCα antisense oligonucleotide, we concluded that the PKCα isoenzyme is an important component of the TGF-β/Smad signaling pathway in melanocytes. PKCα, using suitable enzyme modifiers, may become a target for therapeutic intervention in melanoma.

Physical description

iii, 100 σ. : πιν. ; 30 εκ.

Language

Greek

Subject

Melanocytes

Melanoma therapy

Skin Neoplasms

Μελανοκύτταρα

Νεοπλάσματα δέρματος

Issue date

2007-12-14