Ergebnisse und Implikationen aus dem Modellversuch zum Handel mit Flächenzertifikaten

Die Flächeninanspruchnahme liegt im Vierjahresdurchschnitt der Jahre 2011 bis 2014 mit 69 Hektar pro Tag immer noch mehr als doppelt so hoch wie von der Bundesregierung vor 14 Jahren in der nationalen Nachhaltigkeitsstrategie festgelegt. Vor dem Hintergrund des 30-Hektar-Zieles hat die Bundesregierung in den Koalitionsverträgen der 17. und 18. Legislaturperiode vereinbart, gemeinsam mit den Städten und Gemeinden den kommunalen Handel mit Flächenzertifikaten in einem Modellversuch zu erproben. Der vom Umweltbundesamt beauftragte Modellversuch wurde als Planspiel durchgeführt. Kernstück des Planspiels war ein praxisnahes kontrolliertes Feldexperiment, an dem sich 87 Kommunen beteiligten. In diesem Feldexperiment simulierten die teilnehmenden Kommunen für eigene, real geplante Baugebiete den Flächenzertifikatehandel über einen Zeitraum von 15 Jahren (2014-2028) mittels einer Online-Plattform. Die Ergebnisse zeigen, dass ein Flächenhandelssystem in der Lage ist, die Flächenneuinanspruchnahme effektiv zu verringern. Flächensparziele lassen sich zudem im Verbund aus Planung und flexibler Mengensteuerung effizient erreichen. Die Kommunen konnten die überörtlichen Mengenvorgaben durch den Kauf und Verkauf von Zertifikaten flexibel vor Ort umsetzen. Insgesamt belegen die Ergebnisse, dass ein Flächenhandelssystem geeignet ist, eine nachhaltige Siedlungsentwicklung zu fördern und Kommunalfinanzen zu entlasten

The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage

Chromosome breakage elicits transient silencing of ribosomal RNA synthesis, but the mechanisms involved remained elusive. Here we discover an in trans signalling mechanism that triggers pan-nuclear silencing of rRNA transcription in response to DNA damage. This is associated with transient recruitment of the Nijmegen breakage syndrome protein 1 (NBS1), a central regulator of DNA damage responses, into the nucleoli. We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent. Finally, we provide evidence that Treacle-mediated NBS1 recruitment into the nucleoli regulates rRNA silencing in trans in the presence of distant chromosome breaks

The Effect of Chronic Intermittent Hypoxia on Breast Cancer Cell Gene Expression and Malignant Properties

Breast cancer is the most common cancer in women worldwide and the second most common cancer overall. The most aggressive and most lethal form of breast cancer is inflammatory breast cancer (IBC). The mechanisms underlying the aggressiveness of IBC are still poorly understood. A key feature in the development and progression of breast cancer is the tumor microenvironment that is, amongst others, characterized by a specific composition of the extracellular matrix (ECM) and by the occurrence of tissue hypoxia and oxidative stress. Due to vascular remodeling, leading to structurally and functionally abnormal tumor vessels, tumor cells are exposed to alternating periods of hypoxia and reoxygenation, called chronic intermittent hypoxia (CIH). CIH is a cause of increased reactive oxygen species (ROS) production and has been identified as an important factor in promoting tumor progression and metastasis. However, the molecular mechanisms through which CIH increases the aggressiveness of breast cancer still need to be elucidated. Here, we aimed to assess the impact of CIH on gene expression and cancer cell malignant properties in IBC and non-IBC cell lines. The triple-negative IBC cell line SUM149PT and the estrogen receptor-positive cell line T47D were exposed to 20 cycles of intermittent hypoxia (24 h 0.2% O2, 48 h 21% O2). The effects of CIH on the transcriptomic profile were analyzed in order to obtain insights into signaling pathways, which might be involved in the repeatedly reported enhancement of tumor aggressiveness upon CIH. CIH caused distinct changes in gene expression in both cell lines, with a much higher number of differentially expressed genes in SUM149PT cells compared to T47D cells. In T47D cells, we positively validated the differential gene expression of two ECM proteins which have been linked to tumor progression. In SUM149PT cells, CIH caused a strong upregulation of pro-metastatic genes encoding ECM proteins and inflammatory mediators. We positively validated the CIHmediated increased mRNA and protein expression of the ECM protein tenascin-C (TNC), a key factor in tumor progression. Additionally, for the first time we identified an oxidative stress mediated regulation of TNC in IBC cells, which was dependent on activation of the NF-κB pathway but not on activation of other redox signaling pathways. The observed changes in gene expression suggest an enhanced metastatic potential of SUM149PT cells. Performing in vitro assays to analyze the cancer cell malignant properties, we observed a trend towards a differential attachment behavior of SUM149PT cells following CIH. In summary, this thesis identifies CIH in mediating tumor promotive gene expression changes. Furthermore, CIH and oxidative stress may play an important role in the constitutive activation of NF-κB in IBC, which has repeatedly beenv described in the literature

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

The involvement of estrogen (E2) and hypoxia in tumor progression is well established. Hypoxia has been reported to activate and degrade estrogen receptor alpha (ERα) in breast cancer cells. Furthermore, E2 has been shown to regulate hypoxia-inducible factor (HIF)-1α protein, but its role in HIF-2α regulation remains largely unexplored. In this study, we found that both HIF-2α mRNA and protein were down-regulated in ER positive but not ER negative breast cancer cells upon treatment with E2. The analysis of 690 samples derived from 608 mixed and 82 triple-negative breast cancer patients revealed that high nuclear HIF-2α tumor levels are associated with a worse prognosis specifically in human epidermal growth factor receptor 2 (HER2) and hormone receptor positive patients. Consistently, ERα/HER2 positive breast cancer cells displayed less pronounced downregulation of HIF-2α by E2. Experiments using a histone deacetylase inhibitor indicate that the E2 mediated decrease in HIF-2α mRNA is due to transcriptional repression. A functional estrogen response element (ERE) was identified in the first intron of the gene encoding HIF-2α (EPAS1), suggesting transcriptional co-repressor recruitment by ERα. Our results demonstrate a novel modulation of HIF-2α in breast cancer cells, explaining the opposing regulation between HIF-1α and HIF-2α in hormone-responsive breast cancer

Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition

ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway

High force development augments skeletal muscle signalling in resistance exercise modes equalized for time under tension

How force development and time under tension (TUT) during resistance exercise (RE) influence anabolic signalling of skeletal muscle is incompletely understood. We hypothesized that high force development during RE is more important for post-exercise-induced signalling than submaximal and fatiguing RE with lower force development but similar TUT. Twenty-two male subjects (24 ± 6 years, 181 ± 9 cm, 79 ± 2 kg) performed three distinct RE modes in the fed state with equal TUT but distinct force output: (i) maximal eccentric RE (ECC, n = 7) three sets, eight reps, 100% eccentric dynamic force; (ii) standard RE (STD, n = 7), three sets, 10 reps, 75% dynamic force; and (iii) high fatiguing single-set RE (HIT, n = 8), 20 reps, 100% eccentric-concentric force; vastus lateralis biopsies were collected at baseline, 15, 30, 60, 240 min and 24 h after RE, and the signalling of mechanosensitive and mammalian target of rapamycin (mTOR)-related proteins was determined. The phosphorylation levels of pFAK(Tyr397), pJNK(Thr183/Tyr185), pAKT(Thr308/Ser473), pmTOR(Ser2448), p4E-BP1(Thr37/46), p70s6k(Thr389)/(Ser421/Thr424) and pS6(Ser235/236) were significantly higher in ECC than those in STD and HIT at several time points (P < 0.01). pJNK(Thr183/Tyr185) and pS6(Ser235/236) levels were significantly higher in type II myofibres in ECC compared with STD and HIT. HIT exerted throughout the weakest signalling response. We conclude that high force development during acute RE is superior for anabolic skeletal muscle signalling than fatiguing RE with lower force output but similar TUT. Our results suggest that this response is substantially driven by the higher activation of type II myofibres during RE.status: publishe

Ergebnisse und Implikationen aus dem Modellversuch zum Handel mit Flächenzertifikaten

Die Flächeninanspruchnahme liegt im Vierjahresdurchschnitt der Jahre 2011 bis 2014 mit 69 Hektar pro Tag immer noch mehr als doppelt so hoch wie von der Bundesregierung vor 14 Jahren in der nationalen Nachhaltigkeitsstrategie festgelegt. Vor dem Hintergrund des 30-Hektar-Zieles hat die Bundesregierung in den Koalitionsverträgen der 17. und 18. Legislaturperiode vereinbart, gemeinsam mit den Städten und Gemeinden den kommunalen Handel mit Flächenzertifikaten in einem Modellversuch zu erproben. Der vom Umweltbundesamt beauftragte Modellversuch wurde als Planspiel durchgeführt. Kernstück des Planspiels war ein praxisnahes kontrolliertes Feldexperiment, an dem sich 87 Kommunen beteiligten. In diesem Feldexperiment simulierten die teilnehmenden Kommunen für eigene, real geplante Baugebiete den Flächenzertifikatehandel über einen Zeitraum von 15 Jahren (2014-2028) mittels einer Online-Plattform. Die Ergebnisse zeigen, dass ein Flächenhandelssystem in der Lage ist, die Flächenneuinanspruchnahme effektiv zu verringern. Flächensparziele lassen sich zudem im Verbund aus Planung und flexibler Mengensteuerung effizient erreichen. Die Kommunen konnten die überörtlichen Mengenvorgaben durch den Kauf und Verkauf von Zertifikaten flexibel vor Ort umsetzen. Insgesamt belegen die Ergebnisse, dass ein Flächenhandelssystem geeignet ist, eine nachhaltige Siedlungsentwicklung zu fördern und Kommunalfinanzen zu entlasten