Original title: Retionidy regulovaná transkripce genu a protinádorová aktivita retinoidům podobných molekul
Translated title: Retinoid regulation of target gene transcription and antitumor activity of retinoid related molecules
Authors: Raška, Ivan ; Broulík, Petr (advisor) ; Kostrouch, Zdeněk (referee) ; Pokorný, Jaroslav (referee)
Document type: Doctoral theses
Year: 2007
Language: eng
Abstract: Nuclear Retinoic Acid (RA) Receptors (RARs) activate gene expression through dynamic interactions with coregulators in coordination with the ligand and phosphorylation processes. In the first part of this work, we showed that during RA-dependent activation of the RARq isotype, the pi 60 coactivator pCIP/ACTR/AIВ-1 /RAC-3/TRAM-1 /SRC-3 was phosphorylated by p38MAPK. SRC-3 phosphorylation was correlated to an initial facilitation of RARa-target genes activation, via the control of the dynamics of the interactions of the coactivator with RARa. Then phosphorylation inhibited transcription via promoting the degradation of SRC-3. In line with this, inhibition of p38MAPK markedly enhanced RARa-mediated transcription and RA-dependent induction of cell differentiation. SRC-3 phosphorylation and degradation occurred only within the context of RARa complexes, suggesting that the RAR isotype defined a phosphorylation code through dictating the accessibility of the coactivator to p38MAPK. We proposed a model in which RARa transcriptional activity was regulated by SRC-3 through coordinated events that are fine- tuned by RA and p38MAPK. The retinoid related molecules (RRMs), ST1926 and CD437, are promising anti-cancer agents. In the second part of this work, we compared the RAR trans-activating properties of the two RRMs...

Institution: Charles University Faculties (theses) (web)
Document availability information: Available in the Charles University Digital Repository.
Original record: http://hdl.handle.net/20.500.11956/9828

Permalink: http://www.nusl.cz/ntk/nusl-294274


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Universities and colleges > Public universities > Charles University > Charles University Faculties (theses)
Academic theses (ETDs) > Doctoral theses