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Grover R.,Indian Institute of Science | Grover R.,Institute of Bioinformatics and Applied Biotechnology | Sharathchandra A.,Indian Institute of Science | Ponnuswamy A.,Indian Institute of Science | And 2 more authors.
RNA Biology | Year: 2011

Earlier we have demonstrated the presence of internal ribosome entry site (IRES ) within tumor suppressor p53 mRNA. Here we have mapped the putative secondary structure of p53-IRES RNA using information from chemical probing and nuclease mapping experiments. Additionally, the secondary structure of the IRES element of the wild-type RNA was compared with cancer-derived silent mutant p53 RNAs. These mutations might result in the conformational alterations of p53-IRES RNAs. The results also indicate decreased IRES activities of the mutants as compared to wild-type RNA. Further, it was observed that some of the cytoplasmic trans-acting factors, critical for enhancing IRES function, were unable to bind mutant RNAs as efficiently as to wild-type. Our results suggest that hnRNP C1/C2 binds to p53-IRES and siRNA mediated partial silencing of hnRNP C1/C2 showed appreciable decrease in IRES function and consequent decrease in the level of the corresponding p53 isoform. Interestingly mutant p53 IRES showed lesser binding with hnRNP C1/C2 protein. Finally, upon doxorubicin treatment, the mutant RNAs were unable to show enhanced p53 synthesis to similar extent compared to wild type. Taken together, these observations suggest that mutations occurring in the p53 IRES might have profound implications for de-regulation of its expression and activity. © 2011 Landes Bioscience.

Karthigeyan D.,Jawaharlal Nehru Centre for Advanced Scientific Research | Prasad S.B.B.,Jawaharlal Nehru Centre for Advanced Scientific Research | Shandilya J.,Jawaharlal Nehru Centre for Advanced Scientific Research | Agrawal S.,Institute of Bioinformatics and Applied Biotechnology | Kundu T.K.,Jawaharlal Nehru Centre for Advanced Scientific Research
Medicinal Research Reviews | Year: 2011

The Aurora A kinase belongs to serine/threonine group of kinases, well known for its role in cell cycle, especially in the regulation of mitosis. Numerous substrates of Aurora A kinase have been identified, which are predominantly related to cell cycle progression while some of them are transcription factors. Aurora A-mediated phosphorylation can either directly or indirectly regulate the function of its substrates. There are overwhelming evidences which report overexpression and gene amplification of Aurora A in several human cancers, and suggest that Aurora A could be a bona fide oncogene involved in tumorigenesis. Hence, Aurora A plays wide-ranging roles in both mitosis and its deregulation manifests in cancer progression. These observations have favored the choice of Aurora kinases as a target for cancer therapy. Recently, numerous small molecules have been discovered against Aurora kinases and many have entered clinical trials. Most of these small-molecule modulators designed are specific against either Aurora A or Aurora B, but some are dual inhibitors targeting the ATP-binding site which is highly conserved among the three human homologues of Aurora kinase. In this review, we discuss the physiological functions of Aurora A, interactions between Aurora A kinase and its cellular substrates, tumorigenesis mediated by Aurora A kinase upon overexpression, and small-molecule modulators of Aurora kinase as targets for cancer therapy. © 2010 Wiley Periodicals, Inc.

Nambiar M.,Indian Institute of Science | Goldsmith G.,Institute of Bioinformatics and Applied Biotechnology | Moorthy B.T.,Indian Institute of Science | Lieber M.R.,University of Southern California | And 4 more authors.
Nucleic Acids Research | Year: 2011

The t(14;18) translocation in follicular lymphoma is one of the most common chromosomal translocations. Most breaks on chromosome 18 are located at the 3′-UTR of the BCL2 gene and are mainly clustered in the major breakpoint region (MBR). Recently, we found that the BCL2 MBR has a non-B DNA character in genomic DNA. Here, we show that single-stranded DNA modeled from the template strand of the BCL2 MBR, forms secondary structures that migrate faster on native PAGE in the presence of potassium, due to the formation of intramolecular G-quadruplexes. Circular dichroism shows evidence for a parallel orientation for G-quadruplex structures in the template strand of the BCL2 MBR. Mutagenesis and the DMS modification assay confirm the presence of three guanine tetrads in the structure. 1H nuclear magnetic resonance studies further confirm the formation of an intramolecular G-quadruplex and a representative model has been built based on all of the experimental evidence. We also provide data consistent with the possible formation of a G-quadruplex structure at the BCL2 MBR within mammalian cells. In summary, these important features could contribute to the single-stranded character at the BCL2 MBR, thereby contributing to chromosomal fragility. © 2010 The Author(s).

Jaroslawski S.,Institute of Bioinformatics and Applied Biotechnology | Pai M.,McGill University
Journal of Epidemiology and Global Health | Year: 2012

Serological tests for tuberculosis are inaccurate and WHO has recommended against their use. Although not used by the Revised National TB Control Programme (RNTCP), serodiagnostics are widely used in the private sector in India. A root-cause analysis was undertaken to determine why serological tests are so popular, and seven root causes were identified that can be grouped into three categories: technical/medical, economic, and regulatory. Technical/medical: RNTCP's current low budget does not allow scale-up of the newer, WHO-endorsed technologies. Thus, under the RNTCP, most patients have access to only smear microscopy, a test that is insensitive and underused in the private sector. Because there is no accurate, validated, point-of-care test for TB, serological tests meet a perceived need among doctors and patients. Economic: While imported molecular or liquid culture tests are too expensive, there are no affordable Indian versions on the market, leaving serological tests as the main alternative. Although serological tests are inaccurate, various players along the value chain profit from their use, and this sustains a market for these tests. Regulatory: TB tests are poorly regulated and a large number of serological kits are on the market. Private healthcare in general is poorly regulated, and doctors in the private sector are outside the scope of RNTCP and do not necessarily follow standard guidelines. A clear understanding of these realities should facilitate market-based strategies that can help replace serological tests with accurate, validated tools. © 2012 Ministry of Health, Saudi Arabia.

Jarosawski S.,Creativ Ceutical | Jarosawski S.,Institute of Bioinformatics and Applied Biotechnology | Toumi M.,University of Lyon
BMC Health Services Research | Year: 2011

Background: Market Access Agreements (MAA) between pharmaceutical industry and health care payers have been proliferating in Europe in the last years. MAA can be simple discounts from the list price or very sophisticated schemes with inarguably high administrative burden. Discussion. We distinguished and defined from the health care payer perspective three kinds of MAA: Commercial Agreements (CA), Payment for Performance Agreements (P4P) and Coverage with Evidence Development (CED). Apart from CA, the agreements assumed collection and analysis of real-life health outcomes data, either from a cohort of patients (CED) or on per patient basis (P4P). We argue that while P4P aim at reducing drug cost to payers without a systematic approach to addressing uncertainty about drugs' value, CED were implemented provisionally to reduce payer's uncertainty about value of a medicine within a defined time period. Summary. We are of opinion that while CA and P4P have a potential to reduce payers' expenditure on costly drugs while maintaining a high list price, CED address initial uncertainty related to assessing the real-life value of new drugs and enable a final HTA recommendation or reimbursement and pricing decisions. Further, we suggest that real cost to health care payers of drugs in CA and P4P should be made publicly available in a systematic manner, to avoid a perverse impact of these MAA types on the international reference pricing system. © 2011 Jarosawski and Toumi; licensee BioMed Central Ltd.

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