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Modulation of DNA Binding Affinity of Transcription Factors FOXO and p53 Through Protein-protein Interactions
Hofmanová, Adéla ; Obšil, Tomáš (advisor) ; Pavlíček, Jiří (referee)
5 Abstract The forkhead box "O" (FOXO) proteins are a subclass of the Forkhead family of transcription factors that play a critical role in a variety of cellular processes such as response to cellular stress, gluconeogenesis, cell cycle control, apoptosis, senescence, and repair of DNA damage. They are generally considered to be tumor suppressors. However, it has been shown that they can promote tumorigenesis and induce resistance to the chemotherapeutic agents. Despite many years of research into the biological role of FOXO proteins, a number of questions remain to be answered. For example, whether the slight structural differences observed in the otherwise highly homologous DNA-binding domains of individual FOXO transcription factors affect their DNA binding affinity. Furthermore, it is unclear how protein-protein interactions affect DNA binding affinity of FOXO proteins. Recent study has described the interaction of FOXO transcription factors with the p53 protein. Protein p53 is called the guardian of the genome due to its ability to mediate the response to acute DNA damage. The interaction of FOXO and p53 proteins appears to have a major effect on the DNA binding affinity of both these proteins. Based on this, DNA-binding domains of the human transcription factors FOXO1, FOXO3 and FOXO4 (FOXO1(144-270),...
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Study of interactions of forkhead box O (FOXO) transcription factors with DNA
Hofmanová, Adéla ; Obšil, Tomáš (advisor) ; Pavlíček, Jiří (referee)
This work studies the "O" subgroup of FOX transcription factors, which consists of four members (FOXO1, FOXO3, FOXO4 and FOXO6). They are important regulatory molecules that play a critical role in a number of physiological and pathological processes such as cell cycle control, the body's response to stress, differentiation and apoptosis. Due to their ability to induce cell death, they are generally considered to be tumor suppressors. However, recent studies have shown that they can also induce an opposite effect, i.e. to promote tumor progression or induce resistance to drugs used in the therapy of certain types of tumors. Despite intensive research, a number of questions regarding the function of FOXO proteins still remain unanswered. One question is whether the small structural differences observed in the highly conserved DNA-binding domains (DBD) of FOXO transcription factors affect their DNA- binding affinities. Furthermore, it is unclear whether the recently described protein-protein interaction of FOXO-DBD with the transcription factor p53 affects their DNA-binding affinity. Moreover, the role of the binding site for Mg2+ ion which was found in the crystal structure of FOXO4-DBD:DNA, is also still not understood. To clarify these questions, the DNA-binding domains of the human transcription...
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