Stjepan Uldrijan

Poor therapeutic outcomes and serious side effects, together with acquired resistance to multiple drugs, are common problems of current cancer therapies. Therefore, there is an urgent need for new cancer-targeted drugs, which has led (inter alia) to the development of molecules that can specifically inhibit cyclin-dependent kinases (CDKs). In addition to their cell cycle regulatory functions, CDKs, especially CDK7 and CDK9, play important roles in the regulation of RNA polymerase II-mediated transcription. Here, we report on progress in the preclinical development of CDK inhibitors and their anticancer activities. Special attention is paid to the action mechanisms of the pan-specific CDK inhibitors flavopiridol and roscovitine, which have already entered phase II clinical trials as treatments for various tumours. The links between their ability to inhibit transcription and sensitisation of some types of cancer to apoptosis, mechanisms leading to p53 activation, and their synergistic cooperation with common DNA damaging drugs are also discussed. It has been demonstrated that drug-resistant cancer cells can arise during therapeutic application of small molecule protein kinase inhibitors. Clinical resistance to CDK inhibitors has not yet been described, but by comparing CDKs to other kinases, and CDK inhibitors to other clinically used protein kinase inhibitors, we also discuss possible mechanisms that could lead to resistance to CDK inhibitors.

Cyclin-dependent kinase 7

Cyclin-dependent kinase 4

10.2174/138945010790711950

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Role autofagie v cílené léčbě maligního melanomu

Olga Krupková Jindřiška Hammerová Petr Babula Stjepan Uldrijan

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Functional analysis of Mdm2 suggests differences between Mdm2homodimers and Mdm2/MdmX heterodimers

Pavlína Doleželová Stjepan Uldrijan

MDMX

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Sanguilutine induces caspase-independent type of cell deathmodulated by autophagy

Jindřiška Hammerová Stjepan Uldrijan Eva Táborská Alena Hyršlová Iva Slaninová

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The melanoma-associated antigen 1 (MAGEA1) protein stimulates the E3 ubiquitin-ligase activity of TRIM31 within a TRIM31-MAGEA1-NSE4 complex

Figshare (2015)

Lucie Kozáková Lucie Vondrová Karel Stejskal Panagoula Charalabous Peter Kolesár

The MAGE (Melanoma-associated antigen) protein family members are structurally related to each other by a MAGE-homology domain comprised of 2 winged helix motifs WH/A and WH/B. This family specifically evolved in placental mammals although single homologs designated NSE3 (non-SMC element) exist in most eukaryotes. NSE3, together with its partner proteins NSE1 and NSE4 form a tight subcomplex of the structural maintenance of chromosomes SMC5–6 complex. Previously, we showed that interactions of the WH/B motif of the MAGE proteins with their NSE4/EID partners are evolutionarily conserved (including the MAGEA1-NSE4 interaction). In contrast, the interaction of the WH/A motif of NSE3 with NSE1 diverged in the MAGE paralogs. We hypothesized that the MAGE paralogs acquired new RING-finger-containing partners through their evolution and form MAGE complexes reminiscent of NSE1-NSE3-NSE4 trimers. In this work, we employed the yeast 2-hybrid system to screen a human RING-finger protein library against several MAGE baits. We identified a number of potential MAGE-RING interactions and confirmed several of them (MDM4, PCGF6, RNF166, TRAF6, TRIM8, TRIM31, TRIM41) in co-immunoprecipitation experiments. Among these MAGE-RING pairs, we chose to examine MAGEA1-TRIM31 in detail and showed that both WH/A and WH/B motifs of MAGEA1 bind to the coiled-coil domain of TRIM31 and that MAGEA1 interaction stimulates TRIM31 ubiquitin-ligase activity. In addition, TRIM31 directly binds to NSE4, suggesting the existence of a TRIM31-MAGEA1-NSE4 complex reminiscent of the NSE1-NSE3-NSE4 trimer. These results suggest that MAGEA1 functions as a co-factor of TRIM31 ubiquitin-ligase and that the TRIM31-MAGEA1-NSE4 complex may have evolved from an ancestral NSE1-NSE3-NSE4 complex.

10.6084/m9.figshare.1289848

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Benzo[c]phenanthridine alkaloids induce various types of celldeath in cancer cells

Jindřiška Hammerová Stjepan Uldrijan Olga Krupková Eva Táborská Iva Slaninová

Phenanthridine

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250 Small molecule inhibitors of cellular stress response pathways can modulate viability of malignant melanoma cells

European Journal of Cancer Supplements (2010)

Stjepan Uldrijan Tereza Vaclová Veronika Oralová Jindřiška Hammerová Miroslava Sedláčková

Viability assay

10.1016/s1359-6349(10)71057-0

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Oncoproteins Mdm2 and MdmX: Their roles in the regulation of the p53 tumour suppressor protein

Stjepan Uldrijan Kateřina Cetkovská Lucie Bačáková Karen H. Vousden

MDMX

P53 protein

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Function analysis of newly identified regulator of the MDM2-P53 pathway

Kateřina Cetkovská Hana Šustová Stjepan Uldrijan

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The melanoma-associated antigen 1 (MAGEA1) protein stimulates the E3 ubiquitin-ligase activity of TRIM31 within a TRIM31-MAGEA1-NSE4 complex

Cell Cycle (2015)

Lucie Kozáková Lucie Vondrová Karel Stejskal Panagoula Charalabous Peter Kolesár

The MAGE (Melanoma-associated antigen) protein family members are structurally related to each other by a MAGE-homology domain comprised of 2 winged helix motifs WH/A and WH/B. This family specifically evolved in placental mammals although single homologs designated NSE3 (non-SMC element) exist in most eukaryotes. NSE3, together with its partner proteins NSE1 and NSE4 form a tight subcomplex of the structural maintenance of chromosomes SMC5–6 complex. Previously, we showed that interactions of the WH/B motif of the MAGE proteins with their NSE4/EID partners are evolutionarily conserved (including the MAGEA1-NSE4 interaction). In contrast, the interaction of the WH/A motif of NSE3 with NSE1 diverged in the MAGE paralogs. We hypothesized that the MAGE paralogs acquired new RING-finger-containing partners through their evolution and form MAGE complexes reminiscent of NSE1-NSE3-NSE4 trimers. In this work, we employed the yeast 2-hybrid system to screen a human RING-finger protein library against several MAGE baits. We identified a number of potential MAGE-RING interactions and confirmed several of them (MDM4, PCGF6, RNF166, TRAF6, TRIM8, TRIM31, TRIM41) in co-immunoprecipitation experiments. Among these MAGE-RING pairs, we chose to examine MAGEA1-TRIM31 in detail and showed that both WH/A and WH/B motifs of MAGEA1 bind to the coiled-coil domain of TRIM31 and that MAGEA1 interaction stimulates TRIM31 ubiquitin-ligase activity. In addition, TRIM31 directly binds to NSE4, suggesting the existence of a TRIM31-MAGEA1-NSE4 complex reminiscent of the NSE1-NSE3-NSE4 trimer. These results suggest that MAGEA1 functions as a co-factor of TRIM31 ubiquitin-ligase and that the TRIM31-MAGEA1-NSE4 complex may have evolved from an ancestral NSE1-NSE3-NSE4 complex.

Ring finger

Ubiquitin-Protein Ligases

Immunoprecipitation

10.1080/15384101.2014.1000112

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Citations (44)

Stjepan Uldrijan

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