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Critical Proteins (critical + protein)
Selected AbstractsAnalysis of genomic dose-response information on arsenic to inform key events in a mode of action for carcinogenicityENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2010P. Robinan Gentry Abstract A comprehensive literature search was conducted to identify information on gene expression changes following exposures to inorganic arsenic compounds. This information was organized by compound, exposure, dose/concentration, species, tissue, and cell type. A concentration-related hierarchy of responses was observed, beginning with changes in gene/protein expression associated with adaptive responses (e.g., preinflammatory responses, delay of apoptosis). Between 0.1 and 10 ,M, additional gene/protein expression changes related to oxidative stress, proteotoxicity, inflammation, and proliferative signaling occur along with those related to DNA repair, cell cycle G2/M checkpoint control, and induction of apoptosis. At higher concentrations (10,100 ,M), changes in apoptotic genes dominate. Comparisons of primary cell results with those obtained from immortalized or tumor-derived cell lines were also evaluated to determine the extent to which similar responses are observed across cell lines. Although immortalized cells appear to respond similarly to primary cells, caution must be exercised in using gene expression data from tumor-derived cell lines, where inactivation or overexpression of key genes (e.g., p53, Bcl-2) may lead to altered genomic responses. Data from acute in vivo exposures are of limited value for evaluating the dose-response for gene expression, because of the transient, variable, and uncertain nature of tissue exposure in these studies. The available in vitro gene expression data, together with information on the metabolism and protein binding of arsenic compounds, provide evidence of a mode of action for inorganic arsenic carcinogenicity involving interactions with critical proteins, such as those involved in DNA repair, overlaid against a background of chemical stress, including proteotoxicity and depletion of nonprotein sulfhydryls. The inhibition of DNA repair under conditions of toxicity and proliferative pressure may compromise the ability of cells to maintain the integrity of their DNA. Environ. Mol. Mutagen., 2010. © 2009 Wiley-Liss, Inc. [source] Expression of insulin-like growth factor-binding protein 2 in melanocytic lesionsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 10 2003Huamin Wang Background:, Insulin-like growth factor-1 (IGF-1) is one of the most critical proteins required for the survival, migration, and growth of melanoma cells. IGF-binding protein 2 (IGFBP2), which binds and regulates the function of IGF-1, is upregulated in a dose-dependent manner in melanoma cells treated with IGF-1, suggesting a possible role of IGFBP2 in the pathogenesis of melanoma. Methods:, Tissue microarrays were constructed using formalin-fixed, paraffin-embedded archival tissue blocks from 94 melanocytic lesions: 20 benign nevi, 20 dysplastic nevi, 23 primary melanomas, and 31 metastatic melanomas. IGFBP2 expression was evaluated immunohistochemically using a polyclonal antibody against the C-terminus of IGFBP2. The number of cells and labeling intensity were assessed semiquantitatively. Results:, Positive IGFBP2 labeling was observed in 5.0% of benign nevi, which was significantly lower than in dysplastic nevi (35.0%), primary melanomas (52.2%), or metastatic melanomas (54.8%) (p < 0.05). Among the IGFBP2-positive cases, moderate-to-strong immunostaining was observed in 64.7% of metastatic melanomas and 33.3% of primary melanomas. But none of the dysplastic nevi had moderate-to-strong immunostaining (p < 0.05). Conclusions:, Our study shows that IGFBP2 expression increases from benign and dysplastic nevi to primary and metastatic melanomas and suggests that it may play a role in melanoma progression. [source] Ageing to arrhythmias: conundrums of connections in the ageing heartJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2006Sandra A. Jones The proportion of the population that is elderly continues to increase, leading to an increasing need to address problems chiefly associated with old age. Progressive ageing of the heart is associated with an increasing incidence of arrhythmias and disorders of the normal origin of the heartbeat, the sinoatrial node. This intrinsic pacemaker of the heart has an increasing tendency with age to lose its dominant role in pacing the heart, and regulation of heart rate becomes erratic. This ,sick sinus syndrome' is associated with fainting, palpitations, shortness of breath and sudden death. Current treatment of this condition is by implantation of an artificial pacemaker, an intervention increasingly required with age. The current evidence suggests that the normal heartbeat fails due to changes in the expression of critical proteins that ensure the correct production and conduction of the cardiac action potential. Depletion of a protein directly responsible for providing electrical connections between the cells of the heart, connexin 43, appears to leave the normal cardiac pacemaker disconnected and unable to drive the heart. This process may be associated with age-dependent changes in stress-related signalling. Simple interventions such as exercise could impact on the processes hypothesized to be involved and may offer a means to preserve the stability of the electrical activity of the heart into old age without pharmacological manipulation. [source] Glutathione- S -transferase pi as a model protein for the characterisation of chemically reactive metabolitesPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 2 2008Rosalind E. Jenkins Dr. Abstract Chemically reactive metabolites (CRMs) are thought to be responsible for a number of adverse drug reactions through modification of critical proteins. Methods that defined the chemistry of protein modification at an early stage would provide invaluable tools for drug safety assessment. Here, human GST pi (GSTP) was exploited as a model target protein to determine the chemical, biochemical and functional consequences of exposure to the hepatotoxic CRM of paracetamol (APAP), N -acetyl- p -benzoquinoneimine (NAPQI). Site-specific, dose-dependent modification of Cys47 in native and His-tagged GSTP was revealed by MS, and correlated with inhibition of glutathione (GSH) conjugating activity. In addition, the adaptation of iTRAQ labelling technology to define precisely the quantitative relationship between covalent modification and protein function is described. Multiple reaction monitoring (MRM)-MS of GSTP allowed high sensitivity detection of modified peptides at physiological levels of exposure. Finally, a bioengineered mutant cytochrome P450 with a broad spectrum of substrate specificities was used in an in vitro reaction system to bioactivate APAP: in this model, GSTP trapped the CRM and exhibited both reduced enzyme activity and site-specific modification of the protein. These studies provide the foundation for the development of novel test systems to predict the toxicological potential of CRMs produced by new therapeutic agents. [source] The expression of Bcl-2 family proteins differs between nonsmall cell lung carcinoma subtypesCANCER, Issue 7 2005Helen K. Berrieman Ph.D. Abstract BACKGROUND Proteins of the Bcl-2 family play a key role in the control of apoptosis and carry out both proapoptotic and antiapoptotic functions. However, with the exception of Bcl-2 itself, little is known about the expression of these potentially critical proteins in nonsmall cell lung carcinoma. METHODS Immunohistochemistry was used to study the expression of Bcl-2 and 6 other Bcl-2 family proteins in a pilot series of 41 archival nonsmall cell lung carcinoma specimens (19 adenocarcinomas and 22 squamous cell carcinomas). RESULTS Overexpression of the apoptosis inhibitors Bcl-2 and Bcl-XL was observed in 10 of 41 samples (24%) and in 11 of 41 samples (27%), respectively. Loss of expression of proapoptotic proteins was observed as follows: Bak, 24 of 41 samples (59%); Bad, 21 of 41 samples (51%); Bid, 20 of 41 samples (49%); Bax, 14 of 41 samples (34%); and Bim/Bod, 2 of 41 samples (5%). Statistically significant differences in expression between adenocarcinoma samples and squamous cell carcinoma samples were observed for Bcl-XL (overexpression in 11 of 19 adenocarcinomas [58%] vs. 0 of 22 squamous cell carcinomas [0%]; P < 0.001) and for Bad (loss of expression in 5 of 19 adenocarcinomas [26%] vs. 16 of 22 squamous cell carcinomas [73%]; P = 0.004). CONCLUSIONS Although this was only a pilot study, the results revealed significant differences in the expression of apoptosis-related proteins both between individual samples of nonsmall cell lung carcinoma and between the two main histologic subtypes. Such differences may play a role in the development of lung tumors; and, if it is found that these differences are of clinical importance, then it may be required to regard nonsmall cell lung carcinoma subtypes as separate entities rather than as one disease. Cancer 2005. © 2005 American Cancer Society. [source] | ||||||||||