Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il., tab. ; 30 cm
Aktokardiotokografickou metodou diferencovány jednotlivé pohyby plodu v oblasti hrudníku hlavy a končetin včetně dýchacích pohybů,sledovány i frekvenční změny u jednotlivých typů pohybů.
- Konspekt
- Pediatrie
- NLK Obory
- perinatologie a neonatologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
Molecular biology intelligence unit
[1st ed.] 267 s. : il.
CDK12 is a kinase associated with elongating RNA polymerase II (RNAPII) and is frequently mutated in cancer. CDK12 depletion reduces the expression of homologous recombination (HR) DNA repair genes, but comprehensive insight into its target genes and cellular processes is lacking. We use a chemical genetic approach to inhibit analog-sensitive CDK12, and find that CDK12 kinase activity is required for transcription of core DNA replication genes and thus for G1/S progression. RNA-seq and ChIP-seq reveal that CDK12 inhibition triggers an RNAPII processivity defect characterized by a loss of mapped reads from 3'ends of predominantly long, poly(A)-signal-rich genes. CDK12 inhibition does not globally reduce levels of RNAPII-Ser2 phosphorylation. However, individual CDK12-dependent genes show a shift of P-Ser2 peaks into the gene body approximately to the positions where RNAPII occupancy and transcription were lost. Thus, CDK12 catalytic activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects as a consequence of CDK12 inactivation underlie the genome instability phenotype observed in many cancers.
- MeSH
- cyklin-dependentní kinasy genetika metabolismus MeSH
- fosforylace MeSH
- HCT116 buňky MeSH
- kontrolní body fáze G1 buněčného cyklu genetika fyziologie MeSH
- lidé MeSH
- oprava DNA genetika fyziologie MeSH
- replikace DNA genetika fyziologie MeSH
- RNA-polymerasa II genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Deregulated cell proliferation is the hallmark of cancer, and convergent data from the fields of cell-cycle research and molecular oncology have revealed the key role played by abnormalities of the cell-cycle control genes in multistep tumorigenesis. Along with the p53-mediated DNA damage checkpoint, the G1-governing pathway of D-type cyclins, their partner cyclin-dependent kinases (Cdk), Cdk inhibitors, and the retinoblastoma protein constitute a functional unit and prominent oncogenic target. We have learned a great deal about the molecular basis of G1 phase progression and G1/S transition, their proto-oncogenic defects, and potential clinical significance including diagnostic and prognostic applications and new approaches to gene therapy of cancer.
- MeSH
- biologické modely MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory genetika metabolismus MeSH
- cykliny genetika metabolismus MeSH
- G1 fáze genetika MeSH
- inhibitory enzymů metabolismus MeSH
- lidé MeSH
- nádory genetika metabolismus patologie MeSH
- regulace genové exprese u nádorů MeSH
- retinoblastomový protein metabolismus MeSH
- S fáze genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The ability to preserve genomic integrity is a fundamental feature of life. Recent findings regarding the molecular basis of the cell-cycle checkpoint responses of mammalian cells to genotoxic stress have converged into a two-wave concept of the G1 checkpoint, and shed light on the so-far elusive intra-S-phase checkpoint. Rapidly operating cascades that target the Cdc25A phosphatase appear central in both the initiation wave of the G1 checkpoint (preceding the p53-mediated maintenance wave) and the transient intra-S-phase response. Multiple links between defects in the G1/S checkpoints, genomic instability and oncogenesis are emerging, as are new challenges and hopes raised by this knowledge.
Neuroendokrinní nádory tenkého střeva jsou po slinivce břišní druhou nejčastější lokalizací gastroenteropankreatických neuroendokrinních nádorů. Nádory bez hormonální produkce jsou často zjištěny až v pokročilém stadiu. Maligní potenciál dobře diferencovaných neuroendokrinních nádorů je relativně nízký. Studie CLARINET prokázala antiproliferační účinek Somatulin autogelu 120 mg s.c. 1* za 4 týdny i u tohoto typu nádorů. Naše nemocná dosáhla touto terapií stabilizaci choroby na osm let a celkové přežití zatím činí 12 let a 8 měsíců.
Neuroendocrine tumors of small intestine represent the second most frequent location of gasteroenteropancreatic tumors after pancreas. Non-functioning tumors are very often diagnosed late and in advanced stage. Malignant potential of these well differentiated neuroendocrine tumors is relatively low. Clarinet study confirmed antiproliferative effect of lanreotid autogel 120 mg s.c. once in 4 weeks in this type of tumors. Our patient was stable on this treatment for 8 years and her overall survival till now is 12 years and 8 months.
- Klíčová slova
- studie CLARINET, LANREOTID, SOMATULIN AUTOGEL,
- MeSH
- cyklické peptidy aplikace a dávkování farmakologie MeSH
- karcinoid * diagnostické zobrazování farmakoterapie patologie MeSH
- léky s prodlouženým účinkem MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nemoci ilea farmakoterapie patologie MeSH
- proliferace buněk účinky léků MeSH
- senioři MeSH
- somatostatin * analogy a deriváty MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
A cascade of events is triggered upon the addition of growth factor to quiescent mammalian cells, which ultimately restarts proliferation by inducing the transition from G0/G1 to S-phase. We have studied cyclin D1, a putative G1 cyclin, in normal diploid human fibroblasts. Cyclin D1 accumulated and reached a maximum level before S-phase upon the addition of serum to quiescent cells. The protein was localized to the nucleus, and it disappeared from the nucleus as cells proceeded into S-phase. Microinjection of anti-cyclin D1 antibodies or antisense plasmid prevented cells from entering S-phase, and the kinetics of inhibition showed that cyclin D1 is required at a point in the cell cycle earlier than cyclin A. These results demonstrate that cyclin D1 is a critical target of proliferative signals in G1.
- MeSH
- antisense elementy (genetika) MeSH
- buněčné jádro metabolismus MeSH
- buněčné linie MeSH
- časové faktory MeSH
- cyklin D1 MeSH
- cykliny fyziologie metabolismus MeSH
- DNA biosyntéza MeSH
- fibroblasty cytologie MeSH
- fluorescenční protilátková technika MeSH
- G1 fáze * fyziologie MeSH
- lidé MeSH
- mikroinjekce MeSH
- onkogenní proteiny fyziologie metabolismus MeSH
- plazmidy MeSH
- plíce cytologie fyziologie ultrastruktura MeSH
- S fáze * fyziologie MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- G1 fáze fyziologie MeSH
- myši MeSH
- oocyty fyziologie MeSH
- proteiny buněčného cyklu fyziologie MeSH
- S fáze genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
Embryonic stem cells progress very rapidly through the cell cycle, allowing limited time for cell cycle regulatory circuits that typically function in somatic cells. Mechanisms that inhibit cell cycle progression upon DNA damage are of particular importance, as their malfunction may contribute to the genetic instability observed in human embryonic stem cells (hESCs). In this study, we exposed undifferentiated hESCs to DNA-damaging ultraviolet radiation-C range (UVC) light and examined their progression through the G1/S transition. We show that hESCs irradiated in G1 phase undergo cell cycle arrest before DNA synthesis and exhibit decreased cyclin-dependent kinase two (CDK2) activity. We also show that the phosphatase Cdc25A, which directly activates CDK2, is downregulated in irradiated hESCs through the action of the checkpoint kinases Chk1 and/or Chk2. Importantly, the classical effector of the p53-mediated pathway, protein p21, is not a regulator of G1/S progression in hESCs. Taken together, our data demonstrate that cultured undifferentiated hESCs are capable of preventing entry into S-phase by activating the G1/S checkpoint upon damage to their genetic complement.
- MeSH
- buněčná diferenciace MeSH
- buněčné linie MeSH
- cyklin-dependentní kinasa 2 metabolismus MeSH
- fosfatasy cdc25 metabolismus MeSH
- G1 fáze účinky záření MeSH
- kmenové buňky cytologie metabolismus účinky záření MeSH
- lidé MeSH
- poškození DNA MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- proteinkinasy metabolismus MeSH
- S fáze účinky záření MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
