Latest Publications

@article{paculova_brca1_2017,

title = {BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors.},

author = {Hana Paculová and Juraj Kramara and Šárka Šimečková and Radek Fedr and Karel Souček and Ondřej Hylse and Kamil Paruch and Marek Svoboda and Martin Mistrík and Jiří Kohoutek},

doi = {10.1177/1010428317727479},

issn = {1423-0380 1010-4283},

year  = {2017},

date = {2017-10-01},

journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},

volume = {39},

number = {10},

pages = {1010428317727479},

abstract = {A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination-mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds. Since loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors.},

note = {Place: Netherlands},

keywords = {Animals, BRCA1, BRCA1 Protein/antagonists & inhibitors/*genetics, CDK12, Checkpoint Kinase 1/*genetics, CHK1 inhibitor, Colorectal Neoplasms/drug therapy/*genetics/pathology, Cyclin-Dependent Kinases/antagonists & inhibitors/*genetics, DNA damage response, DNA Damage/drug effects, Drug resistance, Gene Expression Regulation, Gene Silencing, HCT116 Cells, Humans, Mice, Neoplasm/genetics, Neoplastic/drug effects, Poly (ADP-Ribose) Polymerase-1/genetics, Pyrazoles/administration & dosage, Pyrimidines/administration & dosage, Transcription, Xenograft Model Antitumor Assays},

pubstate = {published},

tppubtype = {article}

}

@article{takacova_role_2009,

title = {Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX.},

author = {Martina Takacova and Tereza Holotnakova and Jan Vondracek and Miroslav Machala and Katerina Pencikova and Katarina Gradin and Lorenz Poellinger and Jaromir Pastorek and Silvia Pastorekova and Juraj Kopacek},

doi = {10.1042/BJ20080952},

issn = {1470-8728 0264-6021},

year  = {2009},

date = {2009-04-01},

journal = {The Biochemical journal},

volume = {419},

number = {2},

pages = {419–425},

abstract = {Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1alpha and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1alpha competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.},

note = {Place: England},

keywords = {alpha Subunit, Animals, Antigens, Aryl Hydrocarbon/genetics/metabolism/*physiology, Binding Sites, Blotting, Carbonic Anhydrase IX, Carbonic Anhydrases/genetics/*metabolism, Cell Hypoxia/genetics/*physiology, Cell Line, Chromatin Immunoprecipitation, Genetic/genetics, Humans, Hypoxia-Inducible Factor 1, Mice, Neoplasm/genetics, Polychlorinated Dibenzodioxins/pharmacology, Polymerase Chain Reaction, Promoter Regions, Protein Binding/drug effects, Receptors, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction/drug effects, Tumor, Western},

pubstate = {published},

tppubtype = {article}

}