Biomedical subjects

P Greaney

Publications and source records attributed to P Greaney.

3 recordsLinked to original sources

PubMed2001

Serum response factor cleavage by caspases 3 and 7 linked to apoptosis in human BJAB cells.

Apoptosis involves the cessation of cellular processes, the breakdown of intracellular organelles, and, finally, the nonphlogistic clearance of apoptotic cells from the body. Important for these events is a family of proteases, caspases, which are activated by a proteolytic cleavage cascade and drive apoptosis by targeting key proteins within the cell. Here, we demonstrate that serum response factor (SRF), a transcription factor essential for proliferative gene expression, is cleaved by caspases and that this cleavage occurs in proliferating murine fibroblasts and can be induced in the human B-cell line BJAB. We identify the two major sites at which SRF cleavage occurs as Asp(245) and Asp(254), the caspases responsible for the cleavage and generate a mutant of SRF resistant to cleavage in BJAB cells. Investigation of the physiological and functional significance of SRF cleavage reveals that it correlates with the loss of c-fos expression, whereby neither SRF cleavage fragment retains transcriptional activity. Moreover, the expression of a noncleavable SRF in BJAB cells suppresses apoptosis induced by Fas cross-linking. These results suggest that for apoptosis to proceed, the transcriptional events promoting cell survival and proliferation, in which SRF is involved, must first be inactivated.

3T3 Cells↗

PubMed1990

The expert system approach to predicting protein structure.

Prediction of protein structure is an open-ended problem. Since an approach from first principles cannot be taken in reasonable computer time, short-cuts using further data are necessary. Such data include information about the specific protein in question, and information in databases which are about proteins in general. Is it possible to write a general, flexible 'superalgorithm' which would suit most circumstances? If so, it would seem likely to overcome one of the most understated but nonetheless greatest difficulties associated with molecular modelling and computer-aided drug design--reproducibility. To this end, a 'polymorphic programming environment' has been developed which represents both an expert system and a high-level language for theoretical chemists and molecular biologists. This language is GLOBAL (Ball et al., 1990). In a series of earlier studies, and more recently by means of GLOBAL itself, the nature of reproducibility and its rather surprising limits have been explored, and in general the current status and future potential of protein modelling have been examined.

Expert Systems↗

PubMedDate not supplied

Drug-like annotation and duplicate analysis of a 23-supplier chemical database totalling 2.7 million compounds.

We have implemented five drug-like filters, based on 1D and 2D molecular descriptors, and applied them to characterize the drug-like properties of commercially available chemical compounds. In addition to previously published filters (Lipinski and Veber), we implemented a filter for medicinal chemistry tractability based on lists of chemical features drawn up by a panel of medicinal chemists. A filter based on the modeling of aqueous solubility (>1 microM) was derived in-house, as well as another based on the modeling of Caco-2 passive membrane permeability (>10 nm/s). A library of 2.7 million compounds was collated from the 23 compound suppliers and analyzed with these filters, highlighting a tendency toward highly lipophilic compounds. The library contains 1.6 M unique structures, of which 37% (607,223) passed all five drug-like filters. None of the 23 suppliers provides all the members of the drug-like subset, emphasizing the benefit of considering compounds from various compound suppliers as a source of diversity for drug discovery.

Journal Article↗