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Biomedical subjects

Donald M Black

Publications and source records attributed to Donald M Black.

14 recordsLinked to original sources
PubMed2005

RNAi knockdown of the focal adhesion protein TES reveals its role in actin stress fibre organisation.

TES was originally identified as a candidate tumour suppressor gene and has subsequently been found to encode a novel focal adhesion protein. As well as localising to cell-matrix adhesions, TES localises to cell-cell contacts and to actin stress fibres. TES interacts with a variety of cytoskeletal proteins including zyxin, mena, VASP, talin and actin. There is evidence that TES may function in actin-dependent processes as overexpression of TES results in increased cell spreading and decreased cell motility. Together with TES's interacting partners, these data suggest that TES might be involved in regulation of the actin cytoskeleton. Here, for the first time, we have used RNAi to successfully knockdown TES in HeLa cells and we demonstrate that loss of TES from focal adhesions results in loss of actin stress fibres. Similarly, and as previously reported, RNAi-mediated knockdown of zyxin results in loss of actin stress fibres. TES siRNA treated cells show reduced RhoA activity, suggesting that the Rho GTPase pathway may be involved in the TES RNAi-induced loss of stress fibres. We have also used RNAi to examine the requirement of TES and zyxin for each other's localisation at focal adhesions, and we propose a hierarchy of recruitment, with zyxin being first, followed by VASP and then TES. Cell Motil.

Actins↗
PubMed2004

Characterisation of chicken TES and its role in cell spreading and motility.

Previously we identified TES as a candidate tumour suppressor gene that is located at human chromosome 7q31.1. More recently, we and others have shown TES to encode a novel LIM domain protein that localises to focal adhesions. Here, we present the cloning and functional analysis of the chicken orthologue of TES, cTES. The TES proteins are highly conserved between chicken and human, showing 89% identity at the amino acid level. We show that the cTES protein localised at focal adhesions, actin stress fibres, and sites of cell-cell contact, and GST-cTES can pull-down zyxin and actin. To investigate a functional role for cTES, we looked at the effect of its overexpression on cell spreading and cell motility. Cells overexpressing cTES showed increased cell spreading on fibronectin, and decreased cell motility, compared to RCAS vector transfected control cells. The data from our studies with cTES support our previous findings with human TES and further implicate TES as a member of a complex of proteins that function together to regulate cell adhesion and additionally demonstrate a role for TES in cell motility.

Actins↗
PubMed2003

TES is a novel focal adhesion protein with a role in cell spreading.

Previously, we identified TES as a novel candidate tumour suppressor gene that mapped to human chromosome 7q31.1. In this report we demonstrate that the TES protein is localised at focal adhesions, actin stress fibres and areas of cell-cell contact. TES has three C-terminal LIM domains that appear to be important for focal adhesion targeting. Additionally, the N-terminal region is important for targeting TES to actin stress fibres. Yeast two-hybrid and biochemical analyses yielded interactions with several focal adhesion and/or cytoskeletal proteins including mena, zyxin and talin. The fact that TES localises to regions of cell adhesion suggests that it functions in events related to cell motility and adhesion. In support of this, we demonstrate that fibroblasts stably overexpressing TES have an increased ability to spread on fibronectin.

Animals↗
PubMed2003

The development of combination drugs for atherosclerosis.

The complexity of medical care has led to a dramatic increase in the number of drugs taken by patients. In an effort to improve patient compliance and the effectiveness of clinical care, many drugs are being studied for combination in a single capsule or tablet. The recent success of many combination drugs for hypertension has accelerated the interest in combination drugs for lipids and atherosclerosis. Advicor (Kos Pharmaceuticals, Miami, FL), a combination of nicotinic acid and a statin (mevacor), is the first combination lipid drug. Recently, the United States Food and Drug Administration approved the combination of another statin, pravachol, with aspirin. Therefore, combination drugs are likely to be a significant contribution to clinical practice and drug development.

Arteriosclerosis↗
PubMed2002

Lipoprotein changes with statins.

The effects of statins and other lipid drugs are assessed by their ability to affect specific lipid fractions. Although there has been a great deal written abut the statins, most recent papers have focused on the comparative effects of the statins on triglycerides and high-density lipoprotein cholesterol, or have been concerned with the nonlipid effects of these drugs. In addition, some recent papers have focused on new parameters that may mediate cardiovascular risk, such as high-sensitivity C-reactive protein.

Cholesterol, HDL↗
PubMed2002

A general assessment of the safety of HMG CoA reductase inhibitors (statins).

Few principles in medicine today are as well accepted as the benefits of using statins to reduce cardiovascular risk factors and to prevent cardiovascular disease. The recent withdrawal of a statin (cerivastatin) has lead to a re-examination of all statins, and an attempt to better assess the risk-benefit ratio of this class of drugs. Although the benefits of statin treatment are well known from a myriad of clinical trials, the safety of these compounds has not been an issue since lovastatin was first introduced in 1987. This report provides a brief review of statin safety, and reiterates the excellent profile of this class of drugs.

Clinical Trials as Topic↗
PubMed2002

Gut-acting drugs for lowering cholesterol.

Drugs that indirectly lower blood cholesterol through their actions in the gut have been used for many years. Their utility has been limited by poor tolerability, and hence, poor compliance. New resins are better tolerated and offer an advantage to older drugs. New strategies focusing on reducing serum cholesterol by acting on the gastrointestinal tract may hold even greater promise, combining the safety of nonsystemic agents with the acceptance of statins.

Anticholesteremic Agents↗