Update on HER-2 as a target for cancer therapy: The ERBB2 promoter and its exploitation for cancer treatment

Overexpression of the ERBB2 proto-oncogene is associated with amplification of the gene in breast cancer but increased activity of the promoter also plays a significant role. Members of two transcription factor families (AP-2 and Ets) show increased binding to the promoter in over-expressing cells. Consequently, strategies have been devised to target promoter activity, either through the DNA binding sites for these factors, or through another promoter sequence, a polypurine-polypyrimidine repeat structure. The promoter has also been exploited for its tumour-specific activity to direct the accumulation of cytotoxic compounds selectively within cancer cells. Our current understanding of the ERBB2 promoter is reviewed and the status of these therapeutic avenues is discussed

GAS41 interacts with transcription factor AP-2β and stimulates AP-2β-mediated transactivation

Transcription factor AP-2 regulates transcription of a number of genes involving mammalian development, differentiation and carcinogenesis. Recent studies have shown that interaction partners can modulate the transcriptional activity of AP-2 over the downstream targets. In this study, we reported the identification of GAS41 as an interaction partner of AP-2β. We documented the interaction both in vivo by co-immunoprecipitation as well as in vitro through glutathione S-transferase (GST) pull-down assays. We also showed that the two proteins are co-localized in the nuclei of mammalian cells. We further mapped the interaction domains between the two proteins to the C-termini of both AP-2β and GAS41, respectively. Furthermore, we have identified three critical residues of GAS41 that are important for the interaction between the two proteins. In addition, by transient co-expression experiments using reporter containing three AP-2 consensus binding sites in the promoter region, we found that GAS41 stimulates the transcriptional activity of AP-2β over the reporter. Finally, electrophoretic mobility shift assay (EMSA) suggested that GAS41 enhances the DNA-binding activity of AP-2β. Our data provide evidence for a novel cellular function of GAS41 as a transcriptional co-activator for AP-2β

Large-scale flood risk assessment under different development strategies: the Luanhe River Basin in China

© The Author(s) 2021. Increasing resilience to natural hazards and climate change is critical for achieving many Sustainable Development Goals (SDGs). In recent decades, China has experienced rapid economic development and became the second-largest economy in the world. This rapid economic expansion has led to large-scale changes in terrestrial (e.g., land use and land cover changes), aquatic (e.g., construction of reservoirs and artificial wetlands) and marine (e.g., land reclamation) environments across the country. Together with climate change, these changes may significantly influence flood risk and, in turn, compromise SDG achievements. The Luanhe River Basin (LRB) is one of the most afforested basins in North China and has undergone significant urbanisation and land use change since the 1950s. However, basin-wide flood risk assessment under different development scenarios has not been considered, although this is critically important to inform policy-making to manage the synergies and trade-offs between the SDGs and support long-term sustainable development. Using mainly open data, this paper introduces a new framework for systematically assessing flood risk under different social and economic development scenarios. A series of model simulations are performed to investigate the flood risk under different land use change scenarios projected to 2030 to reflect different development strategies. The results are systematically analysed and compared with the baseline simulation based on the current land use and climate conditions. Further investigations are also provided to consider the impact of climate change and the construction of dams and reservoirs. The results potentially provide important guidance to inform future development strategies to maximise the synergies and minimise the trade-offs between various SDGs in LRB.Natural Environment Research Council (NERC) of the UK Research and Innovation (UKRI) through the Towards a Sustainable Earth (TaSE) programme (NE/S012427/1)

Development of an SDG interlinkages analysis model at the river basin scale: a case study in the Luanhe River Basin, China

While the Sustainable Development Goals (SDG) are broadly framed with 17 goals, the goals and their targets inherently connect with each other forming a complex system. Actions supporting one goal may influence progress in other goals, either positively (synergies) or negatively (trade-offs). Effective managing the synergies and trade-offs is a prerequisite for ensuring policy coherence. This is particular relevant at the river basin scale where the implementation of national policies may generate inequalities at the sub-basin levels, such as the upstream and the downstream. In the existing literature, there is still a lack of methodologies to assess the SDG interlinkages and their differences at the subnational levels. This paper presents a methodology on the development of an SDG interlinkages analysis model at the basin scale and its application to a case study in China’s Luanhe River Basin (LRB). Seven broad areas, namely land use and land cover change, climate change, ecosystem services, flood risks, water sector, urbanisation, and energy, were set as the scope of study. Through a systematic review, key elements of the SDG interlinkages system were identified and their interactions were mapped. The resulting generic SDG interlinkages model were validated with expert survey and stakeholders’ consultation and tailored to the LRB. Quantification of the SDG interlinkages was conducted for 27 counties in the LRB and demonstrated by the results of 3 selected counties located in the upstream, midstream and downstream areas, respectively. The methodology and its applications can be used to support integrated water resource management in river basins

Identification of target genes of transcription factor activator protein 2 gamma in breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Activator protein 2 gamma (AP-2γ) is a member of the transcription factor activator protein-2 (AP-2) family, which is developmentally regulated and plays a role in human neoplasia. AP-2γ has been found to be overexpressed in most breast cancers, and have a dual role to inhibit tumor initiation and promote tumor progression afterwards during mammary tumorigensis.</p> <p>Methods</p> <p>To identify the gene targets that mediate its effects, we performed chromatin immunoprecipitation (ChIP) to isolate AP-2γ binding sites on genomic DNA from human breast cancer cell line MDA-MB-453.</p> <p>Results</p> <p>20 novel DNA fragments proximal to potential AP-2γ targets were obtained. They are categorized into functional groups of carcinogenesis, metabolism and others. A combination of sequence analysis, reporter gene assays, quantitative real-time PCR, electrophoretic gel mobility shift assays and immunoblot analysis further confirmed the four AP-2γ target genes in carcinogenesis group: ErbB2, CDH2, HPSE and IGSF11. Our results were consistent with the previous reports that ErbB2 was the target gene of AP-2γ. Decreased expression and overexpression of AP-2γ in human breast cancer cells significantly altered the expression of these four genes, indicating that AP-2γ directly regulates them.</p> <p>Conclusion</p> <p>This suggested that AP-2γ can coordinate the expression of a network of genes, involving in carcinogenesis, especially in breast cancer. They could serve as therapeutic targets against breast cancers in the future.</p

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

The ERBB2 gene is overexpressed in 30% of breast cancers and this has been correlated with poor prognosis. ERBB2 is upregulated in other cancers such as prostate, pancreas, colon and ovary. In breast cancer cells, the mechanisms leading to ERBB2 gene overexpression are increased transcription and gene amplification. In these cancers, AP-2 transcription factors are involved in ERBB2 overexpression, and AP-2 levels are correlated with p185(c-erbB-2) levels. In this work, we wanted to know if the same molecular mechanisms are responsible for the ERBB2 upregulation in non-breast cancers. We compared ERBB2 gene copy number, p185(c-erbB-2) and mRNA levels with AP-2 levels in several ovary, prostate, colon and pancreas cancer cells. A moderate expression of erbB-2 mRNA and protein were observed in some cells without gene amplification. In contrast to breast cancer cells, AP-2 factors were absent or low in some non-breast cells which did express ERBB2. It is thus likely that AP-2 is not a major player in the increased levels of erbB-2 transcripts in non-breast cancer cells. The transcriptional activity of the ERBB2 promoter in colon and ovary cancer cells was estimated using reporter vectors. The results showed that the promoter regions involved in ERBB2 gene overexpression in breast cancer cells are different from those that lead to the gene upregulation in colon and ovary cancers. In conclusion, our results indicate that different transcriptional and post-transcriptional mechanisms are responsible for the increased levels of erbB-2 transcript and protein in breast and non-breast cancer cells

Dissecting mitosis by RNAi in Drosophila tissue culture cells

Here we describe a detailed methodology to study the function of genes whose products function during mitosis by dsRNA-mediated interference (RNAi) in cultured cells of Drosophila melanogaster. This procedure is particularly useful for the analysis of genes for which genetic mutations are not available or for the dissection of complicated phenotypes derived from the analysis of such mutants. With the advent of whole genome sequencing it is expected that RNAi-based screenings will be one method of choice for the identification and study of novel genes involved in particular cellular processes. In this paper we focused particularly on the procedures for the proper phenotypic analysis of cells after RNAi-mediated depletion of proteins required for mitosis, the process by which the genetic information is segregated equally between daughter cells. We use RNAi of the microtubule-associated protein MAST/Orbit as an example for the usefulness of the technique

Theorizing construction industry practice within a disaster risk reduction setting: is it a panacea or an illusion?

Construction industry practice is strongly influenced by the culture surrounding its operations and, with the prevailing emphasis on achieving efficiency, there is a strong focus on outcome metrics such as profitability and employee productivity. With the recent increases in natural hazard events worldwide, and the likelihood that this will worsen still further with anticipated climate changes, the industry is increasingly contributing to building resilience within disaster-affected communities. Existing industry expertise, its educational approaches and the related theoretical frameworks, however, all require adjustment if these changing needs are to be fully addressed. Most importantly, an agenda shift is required from the philosophical side and a more pragmatic approach is needed if community resilience goals and objectives are to be met, rather than the narrower focus of the current metrics-driven management system. A synthesis of the current literature is therefore presented, along with relevant case histories illustrating how such an agenda shift within a disaster management context may influence the development of appropriate theory, as well as impacting upon grass-roots educational requirements. The research concludes by discussing how the ‘mainstreaming’ of disaster management within construction industry practice could drive forward developments in theorizing expertise and educational provisions across the constituent discipline