PIPKIγ Regulates Focal Adhesion Dynamics and Colon Cancer Cell Invasion

Focal adhesion assembly and disassembly are essential for cell migration and cancer invasion, but the detailed molecular mechanisms regulating these processes remain to be elucidated. Phosphatidylinositol phosphate kinase type Iγ (PIPKIγ) binds talin and is required for focal adhesion formation in EGF-stimulated cells, but its role in regulating focal adhesion dynamics and cancer invasion is poorly understood. We show here that overexpression of PIPKIγ promoted focal adhesion formation, whereas cells expressing either PIPKIγK188,200R or PIPKIγD316K, two kinase-dead mutants, had much fewer focal adhesions than those expressing WT PIPKIγ in CHO-K1 cells and HCT116 colon cancer cells. Furthermore, overexpression of PIPKIγ, but not PIPKIγK188,200R, resulted in an increase in both focal adhesion assembly and disassembly rates. Depletion of PIPKIγ by using shRNA strongly inhibited formation of focal adhesions in HCT116 cells. Overexpression of PIPKIγK188,200R or depletion of PIPKIγ reduced the strength of HCT116 cell adhesion to fibronection and inhibited the invasive capacities of HCT116 cells. PIPKIγ depletion reduced PIP2 levels to ∼40% of control and PIP3 to undetectable levels, and inhibited vinculin localizing to focal adhesions. Taken together, PIPKIγ positively regulates focal adhesion dynamics and cancer invasion, most probably through PIP2-mediated vinculin activation

FAK/src-Family Dependent Activation of the Ste20-Like Kinase SLK Is Required for Microtubule-Dependent Focal Adhesion Turnover and Cell Migration

Cell migration involves a multitude of signals that converge on cytoskeletal reorganization, essential for development, immune responses and tissue repair. Using knockdown and dominant negative approaches, we show that the microtubule-associated Ste20-like kinase SLK is required for focal adhesion turnover and cell migration downstream of the FAK/c-src complex. Our results show that SLK co-localizes with paxillin, Rac1 and the microtubules at the leading edge of migrating cells and is activated by scratch wounding. SLK activation is dependent on FAK/c-src/MAPK signaling, whereas SLK recruitment to the leading edge is src-dependent but FAK independent. Our results show that SLK represents a novel focal adhesion disassembly signal

Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards

Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence-based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard

Assessment protocol : overheating in dwellings

This assessment protocol has been produced by the Building Research Establishment during the course of a research project on behalf of the BRE Trust in collaboration with the BRE Centre for Resilience. It provide a process to be used to determine the seriousness of a potential threat to health from exposure to high temperatures within a dwelling. It should be read in conjunction with the guidance document on excess heat, which defines excess heat, its causes and potential preventative measures

Guidance document : overheating in dwellings

This guidance document has been produced by the Building Research Establishment during the course of a research project on behalf of the BRE Trust in collaboration with the BRE Centre for Resilience. It defines the characteristics of excess heat, considers the potential for harm arising from excess heat and the associated health impacts. It also identifies the causes of excess heat and potential preventative measures. An accompanying assessment protocol is available in order to provide a process to be used to determine the seriousness of a potential threat to health from exposure to high temperatures within a dwelling

Housing in Europe : the consequences of poor accommodation

This report aims to improve understanding of the true cost of inadequate housing to EU Member States and to suggest policy initiatives that might help address its social and financial consequences. The full impact of poor housing tends to be evident only in the longer term, and the savings to publicly funded services, the economy and society that investment in good quality accommodation can deliver are not always obvious. While housing policies are the prerogative of national governments, many Member States face similar challenges in this field. In some, projects to improve inadequate housing have already provided valuable practical experience that can usefully be shared, and this report presents eight such case studies. While improving poor living conditions would be costly, the report suggests the outlay could be recouped quite quickly from savings on healthcare and a range of publicly funded services – in the EU as a whole, for every €3 invested in improving housing conditions, €2 would come back in savings in one year. An executive summary is available - see Related content

Will drivers for home energy efficiency harm occupant health?

The UK government has committed to an 80% reduction in carbon emissions by 2050, with housing accounting for 27% of total current emissions. There are several drivers both to reduce emissions from homes and to reduce fuel poverty, promoting a range of building and behavioural measures in homes. The health benefits of warmer homes in winter have been described, but there has been less consideration of the potential negative impacts of some of these measures. We examine the changes in UK homes, and the possible consequences for health. The main concerns for health surround the potential for poor indoor air quality if ventilation is insufficient and the possible risks of overheating in heatwave conditions. This paper notes a limited evidence base and the need for further research on the health effects of energy-efficient homes, particularly with regard to ventilation