Are Diadenosine Polyphosphates and/or FHIT Involved in Anoikis?

Abstract

Anoikis protects the organism against the inappropriate growth of epithelial cells released during normal turnover. Downstream of the "anoikis receptors", many signaling components have been identified, but many others are undoubtedly remaining to be discovered. One of the primary limitations appears to be the tendency to focus on two second messengers, phosphorylation and lipids. While these are unquestionably important, many other signaling mediators are emerging at present, whose role in anoikis is totally unexplored, even though they (and others) may potentially be essential to the mechanism. In this light, we propose to examine the role of a class of molecules represented by diadenosine triphosphate (Ap3A) and diadenosine tetraphosphate (Ap4A) in anoikis. These molecules occur in all organisms, accumulate in response to cellular stress, and have quite recently been implicated in apoptosis in mammalian cells. - A tumor suppressor gene that is frequently altered in various human cancers, FHIT (Fragile Histidine Triad), is an Ap3A and Ap4A hydrolase, connecting these dinucleotides with cancer. ApnAs probably act as cofactors for Fhit's effector function (analogous to the function of GIP for ras.) The FHIT gene is altered in 82% of BRCA2-linked breast carcinomas and 40% of sporadic cases, implicating FHIT as a breast cancer-relevant, ApnA-regulated protein that may be involved in regulating apoptosis. Given the particular importance of anoikis-resistance in the development of breast cancer, the purpose of this IDEA project is to determine whether Ap3A/Ap4A and/or FHIT can regulate anoikis in normal and transformed mammary epithelial cells; the second goal is to establish the functional relationship between mammary tumor-related oncogenes and this new component in regulating anoikis.

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Document Details

Document Type
Technical Report
Publication Date
Jun 01, 2002
Accession Number
ADA407403

Entities

People

  • Steven M. Prisch

Organizations

  • Sanford Burnham Prebys Medical Discovery Institute

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  • Biology

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