Trends in Endocrinology & Metabolism
ReviewNuclear receptors in cell life and death
Section snippets
Growth regulation by NRs: (patho)physiological phenomena
NRs comprise two principal categories: those that stimulate growth and those that interfere negatively with cell proliferation. ers and ars are predominantly growth-stimulatory receptors in the major target organs, such as breast and prostate, which is why anti-hormonal therapies are used in the corresponding (hormone-responsive) cancers. By contrast, grs are mainly antiproliferative because they induce apoptosis in lymphoid cells; thus, gc agonists are useful as anti-leukemia and
Molecular basis and therapeutic perspective of the growth-regulatory potential of NRs
Cell growth is the consequence of the relative importance of the signaling pathways that control cell proliferation, death and survival. NRs can interfere positively or negatively with each of these events, or even simultaneously with two or more, in some cases in a temporal manner. There is some understanding of the molecular mechanisms by which NRs regulate the programs controlling growth; that is, cell cycle progression and arrest, cell survival and apoptosis.
Summary
NRs have a major impact on growth regulation in embryogenesis, organ development and homeostasis and, in particular, life and death decisions in many cell types. They are prime pharmacological targets because, in addition to their regulatory power, their ligands are small and amenable to combinatorial chemistry. Importantly, ligand design can dissociate receptor-associated function, thus allowing specification of a desired pharmacological effect 113, 114. To exploit the ability of NRs to
Acknowledgements
The authors thank Michel Lanotte and colleagues for efficient collaboration and exchange of ideas. LA thanks INSERM and the Italian Government (L. R. n. 41, 1999) for support. Work at the IGBMC was supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg and Bristol-Myers Squibb.
Glossary
- AD
- activation domain, one or more ADs can constitute an AF.
- AF-1
- activation function 1 in the N-terminal region A/B of nuclear receptors.
- AF-2
- activation function 2 in the LBD of nuclear receptors.
- Akt
- serine/threonine kinase with SH2 and PH domains, activated by inositol (1,4,5) trisphosphate kinase downstream of insulin and other growth factor receptors; Akt phosphorylates glycogen synthase kinase 3 and is involved in stimulation of Ras and control of cell survival.
- APL
- acute promyelocytic leukemia.
- AR
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