Genetic modelling of the PTEN/AKT pathway in cancer research

Experimental Therapeutics Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Clinical and Translational Oncology (Impact Factor: 1.6). 11/2008; 10(10):618-27. DOI: 10.1007/s12094-008-0262-1
Source: PubMed

ABSTRACT The focus on targeted therapies has been fuelled by extensive research on molecular pathways and their role in tumorigenesis. Novel models of human cancer have been created to evaluate the role of specific genes in the different stages of cancer. Currently, mouse modelling of human cancer is possible through the expression of oncogenes, specific genetic mutations or the inactivation of tumour suppressor genes, and these models have begun to provide us with an understanding of the molecular pathways involved in tumour initiation and progression at the physiological level. Additionally, these mouse models serve as an excellent system to evaluate the efficacy of currently developed molecular targeted therapies and identify new potential targets for future therapies. The PTEN/AKT pathway is implicated in signal transduction through tyrosine kinase receptors and heterotrimeric G protein-linked receptors. Deregulation of the PTEN/AKT pathway is a common event in human cancer. Despite the abundant literature, the physiological role of each element of the pathway has begun to be uncovered thanks to genetically engineered mice. This review will summarise some of the key animal models which have helped us to understand this signalling network and its contribution to tumorigenesis.

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    ABSTRACT: When PI3K (phosphatidylinositol-3 kinase) is activated by receptor tyrosine kinases, it phosphorylates PIP2 to generate PIP3 and activates the signaling pathway. Phosphatase and tensin homolog deleted on chromosome 10 dephosphorylates PIP3 to PIP2, and thus, negatively regulates the pathway. AKT (v-akt murine thymoma viral oncogene homolog; protein kinase B) is activated downstream of PIP3 and mediates physiological processes. Furthermore, substantial crosstalk exists with other signaling networks at all levels of the PI3K pathway. Because of its diverse array, gene mutations, and amplifications and also as a consequence of its central role in several signal transduction pathways, the PI3K-dependent axis is frequently activated in many tumors and is an attractive therapeutic target. The preclinical testing and analysis of these novel therapies requires appropriate and well-tailored systems. Mouse models in which this pathway has been genetically modified have been essential in understanding the role that this pathway plays in the tumorigenesis process. Here, we review cancer mouse models in which the PI3K/AKT pathway has been genetically modified.
    Frontiers in Oncology 09/2014; 4:252. DOI:10.3389/fonc.2014.00252
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    ABSTRACT: Programmed cell death eliminates unneeded and dangerous cells in a timely and effective manner during development. In this review, we examine the role cell death plays during development in worms, flies and mammals. We discuss signaling pathways that regulate developmental cell death, and describe how they communicate with the core cell death pathways. In most organisms the majority of developmental cell death is seen in the nervous system. Therefore we focus on what is known about the regulation of developmental cell death in this tissue. Understanding how the cell death is regulated during development may provide insight into how this process can be manipulated in the treatment of disease. Copyright © 2015. Published by Elsevier Ltd.
    Seminars in Cell and Developmental Biology 02/2015; DOI:10.1016/j.semcdb.2015.02.001 · 5.97 Impact Factor


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May 21, 2014

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