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Metabolic alterations in cancer cells and their implications in the therapy of acute leukemias
Harárová, Alžbeta ; Starková, Júlia (advisor) ; Mrvová, Silvia (referee)
Cancer metabolism differs from that of the healthy cells in several aspects. Aerobic glycolysis (e.g. converting pyruvate to lactate under normoxic conditions) was the first described metabolic alteration of cancer cells. Metabolic alterations have since been described in the tricarboxylic acid cycle, oxidative phosphorylation, in the metabolism of amino acids (especially glutamine, asparagine and serine) and also in the metabolism of fatty acids and cholesterol. The common feature of these changes is the tendency to prefer anabolic pathways, thus enabling fast proliferation of cancer cells. The study of cancer metabolism is particularly important in the case of cancer cells that show resistance to treatment, as their aberrant metabolism is not only a potential diagnostic marker but also a potential therapeutic target. The majority of metabolic alterations have been described for the first time in solid tumors, whereas only recently has the metabolism of acute leukamias gained more attention. Asparaginase is an example of a chemotherapeutic agent that targets a metabolic alteration of leukemic cells. Distinct metabolic profile is also associated with the glucocorticoid resistance. Detailled study of the metabolic alterations of leukemic cells has elucitated the mechanisms of the asparaginase and...
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Approaches to mTOR pathway inhibition in acute leukemic cell lines
Kolejáková, Veronika ; Mrvová, Silvia (advisor) ; Kojzarová, Martina (referee)
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase regulating cell growth, proliferation, metabolism and survival. The mTOR pathway integrates stimuli from growth factors, nutrients, and cellular energy status and leads to downstream activation of Akt, 4E-BP1 and S6K. Phosphorylation of 4E-BP1 and S6K results in increased protein synthesis in addition to ribosome biogenesis and plays an important role in cell cycle progression. mTOR pathway is overactivated in numerous cancer types including the acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), which are both characterized by abnormal proliferation of white blood cells and low patient survival rate. Three distinct approaches that differ in efficiencies and research stages have been used to inhibit the mTOR pathway. Rapamycin and its derivatives are the most common inhibitors, but since they are not entirely specific, they provide only limited desirable outcomes. Dual inhibitors targeting mTOR as well as PI3K pathway have had several successes in treating both AML and ALL. However, the new generation of inhibitors such as PP-242 and Torin-1 are providing the most hopeful prospects for mTOR inhibition and long-term remission of acute leukemia.
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Regulation of transcription in mycobacteria.
Páleníková, Petra ; Krásný, Libor (advisor) ; Mrvová, Silvia (referee)
The bacterial cell has to be able to cope with environmental changes. Adaptation to these changes is achieved by changes in gene expression. Gene expression is regulated mostly at the level or transcription initiation. Transcription initiation depends on the sequence of promoters and is regulated by alternative sigma factors and many transcription factors acting either as activators or repressors. This work describes various ways of transcription regulation in the bacterial genus Mycobacterium that includes deathly pathogens such as M. tuberculosis and M. leprae. The typical characteristics of this genus are poorly conserved promoters, a high number of sigma and transcription factors, the presence of two-component systems and a lot of small RNAs that have not been characterized in detail so far.
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Study of translation initiation factors of eIF4E protein family in relation to acute lymphoblastic leukemias and ontogenesis of Tribolium castaneum
Mrvová, Silvia ; Mašek, Tomáš (advisor) ; Doležel, David (referee) ; Čuřík, Nikola (referee)
Translation initiation is one of the key moment in the cell at which many translation initiation factors participate. This step must be carefully regulated not to waste energy. Also excess or lack of many proteins can lead to different diseases. Translation initiation factor eIF4E is important mainly because of its ability to bind a cap and eIF4G and therefore its role in translation initiation. There are three isoforms in human cells - eIF4E1, eIF4E2, eIF4E3. eIF4E1 has been the most studied isoform; however the attention nowadays is drawn to the other two and their functions in cells as well. Upregulation of eIF4E1 is connected with different types of tumors or malignancies. The role of eIF4E isoforms comes to the fore, there has been a research in many model organisms, for example D. melanogaster or C. elegans where the individual isoforms have a role in maturation of oocytes, in forming body axes etc. I focused on all three isoforms of eIF4E, their 3′-UTR regions in lymphoblastic leukemic cells and the utilization of polyadenylation signals of these transcripts because there were shown several types of post-transcriptional regulations, for example stabilization of transcripts by HuR protein. I characterized 3′-UTR regions of eIF4E1, eIF4E2 and eIF4E3 transcripts and confirmed utilization of...
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Oncoretroviruses: tumor transformation mechanisms of hematopoietic cells resulting in leukaemia
Gašpareková, Mária ; Bendová, Michaela (advisor) ; Mrvová, Silvia (referee)
HTLV-1 and FeLV are retroviruses, which are able to transform host cells and cause cancer, mostly leukemia, in infected organism. Belonging to Retroviridae family and both using very similar genome, these viruses developed different ways to reach transformation of infected cells. While FeLV uses insertional activation close to cellular proto-oncogenes in order to regulate transcription of these genes or carries cellular oncogene in its genome, HTLV-1 codes viral proteins which are able to regulate many processes of the cell. One of these proteins is Tax, which regulates many events in the cell, such as signalization, cell cycle, apoptosis and others. Another protein responsible for oncogenesis is HBZ, which is transcribed from antisense strand of proviral DNA. In the end HTLV-1 and FeLV strategies causing cancer are compared with some other leukemic retroviruses in order to show, that molecular strategies described on examples of HTLV-1 and FeLV are more or less common also for other oncogenic retroviruses. Key words: HTLV-1, FeLV, transformation, leukaemia, tumor, oncogene
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Metabolic alterations in cancer cells and their implications in the therapy of acute leukemias
Harárová, Alžbeta ; Starková, Júlia (advisor) ; Mrvová, Silvia (referee)
Cancer metabolism differs from that of the healthy cells in several aspects. Aerobic glycolysis (e.g. converting pyruvate to lactate under normoxic conditions) was the first described metabolic alteration of cancer cells. Metabolic alterations have since been described in the tricarboxylic acid cycle, oxidative phosphorylation, in the metabolism of amino acids (especially glutamine, asparagine and serine) and also in the metabolism of fatty acids and cholesterol. The common feature of these changes is the tendency to prefer anabolic pathways, thus enabling fast proliferation of cancer cells. The study of cancer metabolism is particularly important in the case of cancer cells that show resistance to treatment, as their aberrant metabolism is not only a potential diagnostic marker but also a potential therapeutic target. The majority of metabolic alterations have been described for the first time in solid tumors, whereas only recently has the metabolism of acute leukamias gained more attention. Asparaginase is an example of a chemotherapeutic agent that targets a metabolic alteration of leukemic cells. Distinct metabolic profile is also associated with the glucocorticoid resistance. Detailled study of the metabolic alterations of leukemic cells has elucitated the mechanisms of the asparaginase and...
|
|
|
Approaches to mTOR pathway inhibition in acute leukemic cell lines
Kolejáková, Veronika ; Mrvová, Silvia (advisor) ; Kojzarová, Martina (referee)
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase regulating cell growth, proliferation, metabolism and survival. The mTOR pathway integrates stimuli from growth factors, nutrients, and cellular energy status and leads to downstream activation of Akt, 4E-BP1 and S6K. Phosphorylation of 4E-BP1 and S6K results in increased protein synthesis in addition to ribosome biogenesis and plays an important role in cell cycle progression. mTOR pathway is overactivated in numerous cancer types including the acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), which are both characterized by abnormal proliferation of white blood cells and low patient survival rate. Three distinct approaches that differ in efficiencies and research stages have been used to inhibit the mTOR pathway. Rapamycin and its derivatives are the most common inhibitors, but since they are not entirely specific, they provide only limited desirable outcomes. Dual inhibitors targeting mTOR as well as PI3K pathway have had several successes in treating both AML and ALL. However, the new generation of inhibitors such as PP-242 and Torin-1 are providing the most hopeful prospects for mTOR inhibition and long-term remission of acute leukemia.
|
|
|
Regulation of transcription in mycobacteria.
Páleníková, Petra ; Krásný, Libor (advisor) ; Mrvová, Silvia (referee)
The bacterial cell has to be able to cope with environmental changes. Adaptation to these changes is achieved by changes in gene expression. Gene expression is regulated mostly at the level or transcription initiation. Transcription initiation depends on the sequence of promoters and is regulated by alternative sigma factors and many transcription factors acting either as activators or repressors. This work describes various ways of transcription regulation in the bacterial genus Mycobacterium that includes deathly pathogens such as M. tuberculosis and M. leprae. The typical characteristics of this genus are poorly conserved promoters, a high number of sigma and transcription factors, the presence of two-component systems and a lot of small RNAs that have not been characterized in detail so far.
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Study of translation initiation factors eIF3 and eIF4E in leukemic cell lines
Mrvová, Silvia ; Mašek, Tomáš (advisor) ; Haškovec, Cedrick (referee)
eIF3 and eIF4E are very important eukaryotic translation initiation factors. eIF3 is practically involved in every step of translation initiation, eIF4E is important mainly for its ability to bind the cap. Mammalian factor eIF3 consists of thirteen subunits, many subunits have a function apart from translation, such as in apoptosis and mitosis. It was proved that upregulated or downregulated expression of some subunits as well as upregulated expression of eIF4E is linked with different types of tumours and malignancies in human. In the first part of my work, I was examining the amount of transcripts of subunits eIF3a, b, d, e, f, g, h, i and j in cell lines which are used for study of acute lymphoblastic leukaemia. I tried to find if there is a difference in the amount of trancripts between lines or between lines and control line in these subunits. According to experiments and statistical analysis, I proved increased amount of mRNA for eIF3b subunit in control cell line NC-NC in comparison with other used leukaemic cell line except from line NALM6. Other differences were not statistically important. In the second part of my work, I was analysing 3' UTR region of transcripts of eIF4E1 and utilising of polyadenylation signals in this trancript. I used the leukeamic cell lines again. The experiments clearly...
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