BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM

Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17

Carbonic anhydrase IX (CA IX) is a transmembrane protein whose expression is strongly induced by hypoxia in a broad spectrum of human tumours. It is a highly active enzyme functionally involved in both pH control and cell adhesion. Its presence in tumours usually indicates poor prognosis. Ectodomain of CA IX is detectable in the culture medium and body fluids of cancer patients, but the mechanism of its shedding has not been thoroughly investigated. Here, we analysed several cell lines with natural and ectopic expression of CA IX to show that its ectodomain release is sensitive to metalloprotease inhibitor batimastat (BB-94) and that hypoxia maintains the normal rate of basal shedding, thus leading to concomitant increase in cell-associated and extracellular CA IX levels. Using CHO-M2 cells defective in shedding, we demonstrated that the basal CA IX ectodomain release does not require a functional TNFα-converting enzyme (TACE/ADAM17), whereas the activation of CA IX shedding by both phorbol-12-myristate-13-acetate and pervanadate is TACE-dependent. Our results suggest that the cleavage of CA IX ectodomain is a regulated process that responds to physiological factors and signal transduction stimuli and may therefore contribute to adaptive changes in the protein composition of tumour cells and their microenvironment

Koncepcja projektowa konstrukcji budynku, oceny ekologicznej i rozwiązań materiałowych

Designing a building requires an interplay of architecture and design parameters to create an artificial material environment. Each architectural and engineering design has direct impact on the indoor climate environment and is a key determinant of operational performance of buildings throughout their life. The following paper presents one important component of the process of reducing the operating energy performance of buildings within a designated period of their exploitation as packaging design of buildings and their physical and technical characteristics, which are intended design concept and building material solutions.Projektowanie budynku wymaga współgrania rozwiązań architektonicznych z wymaganymi parametrami projektowymi w celu stworzenia optymalnego środowiska wnętrz. Każde architektoniczne i konstrukcyjne rozwiązanie ma bezpośredni wpływ na mikroklimat oraz kluczowe znaczenie dla kształtowania się parametrów eksploatacyjnych budynku w cyklu jego życia. Istotnym elementem w procesie redukcji zużycia energii w planowanym okresie eksploatacji jest wybór odpowiednich rozwiązań materiałowo-konstrukcyjnych

Energetyczny i środowiskowy profil budynku o niskim zapotrzebowaniu na energię – studium przypadku

Integrated building design should take into account environmental, social and economic dimensions of sustainability. Building design from energy performance ranges from architectural design to the application of technologies for energy conservation. Many applications are focused on insulation of facades, roofs and floors to those that are used systems for renewable energy sources. The aim of the innovations is not only energy saving but also reduces costs and preserves natural resources. One key element of low-energy building design is using the basic form and enclosure of a building to save energy while enhancing occupant comfort. Besides energy need for building operation the significant part of the total energy is energy used in the extraction, processing and transportation of materials used in buildings. This study is aimed to analyze the building materials and structures in terms of embodied environmental impacts and monitoring of physical factors of indoor environment. The paper deals with evaluation of environmental and energy indicators in selected low-energy family house and its optimization in order to reduction of environmental impacts.Zintegrowany projekt budowlany powinien uwzględniać środowiskowe, społeczne i ekonomiczne aspekty zrównoważonego rozwoju. Projektowanie budynków w zakresie efektywności energetycznej obejmuje różne aspekty, począwszy od projektu architektonicznego aż po wykorzystanie technologii związanych z oszczędzaniem energii. Wiele uwagi przywiązuje się do prawidłowej izolacji ścian, dachów i podłóg aż po zastosowanie systemów wykorzystujących odnawialne źródła energii. Celem innowacji jest nie tylko oszczędzanie energii, ale również obniżenie kosztów i ochrona zasobów naturalnych. Niniejsze opracowanie koncentruje się na analizie materiałów budowlanych i konstrukcji w odniesieniu ich do oddziaływania na środowisko oraz na monitorowaniu fizycznych parametrów środowiska wewnętrznego. W pracy przedstawiono ocenę wskaźników energetycznych i środowiskowych w wybranym budynku o niskim zapotrzebowaniu na energię i ich optymalizację w celu zmniejszenia oddziaływania na środowisko