Nuclear receptors in cell life and death

doi:10.1016/S1043-2760(01)00502-1

Trends in Endocrinology & Metabolism

Volume 12, Issue 10, 1 December 2001, Pages 460-468

https://doi.org/10.1016/S1043-2760(01)00502-1 Get rights and content

Abstract

The balance between cell proliferation and programmed cell death (apoptosis) determines body patterns during animal development and controls compartment sizes, tissue architecture and remodeling. The removal of primordial structures by apoptosis allows the organism to develop sex specifically and to adapt for novel functions at later stages; apoptosis also limits the size of evolving structures. It is a ubiquitous function that is essential for all cells. Although inappropriate regulation or execution of apoptosis leads to disease, such as cancer, there is now evidence for its great therapeutic potential. This would be particularly true if apoptosis could be targeted at defined cell compartments, rather than acting ubiquitously like chemotherapy. Here, we discuss the potential of nuclear receptor ligands, many of which act through their cognate receptors in defined body compartments as modulators of cell life and death, with special emphasis on the molecular pathways by which these receptors affect cell-cycle progression, survival and apoptosis.

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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Trends in Endocrinology & Metabolism

ReviewNuclear receptors in cell life and death

Abstract

Section snippets

Growth regulation by NRs: (patho)physiological phenomena

Molecular basis and therapeutic perspective of the growth-regulatory potential of NRs

Summary

Acknowledgements

Glossary

J. Steroid Biochem. Mol. Biol.

Bailliere's Best Pract. Res. Clin. Obstet. Gynaecol.

Lancet

Mod. Pathol.

J. Steroid Biochem. Mol. Biol.

Biol. Psychiatry

J. Chem. Neuroanat.

Methods Enzymol.

Cell

Dev. Biol.

Semin. Hematol.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Cell

Semin. Cell Dev. Biol.

Blood

Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens

Endocrinology

Estrogen receptor-null mice: what have we learned and where will they lead us?

Endocr. Rev.

Crosstalk between the insulin-like growth factors and estrogens in breast cancer

J. Mammary Gland Biol. Neoplasia

Role of hormones in mammary cancer initiation and progression

J. Mammary Gland Biol. Neoplasia

Estrogen and the risk of breast cancer

New Engl. J. Med.

Estrogen use and cancer incidence: a review

Cancer Invest.

The estrogen receptor: a logical target for the prevention of breast cancer with antiestrogens

J. Mammary Gland Biol. Neoplasia

Breast cancer chemoprevention: beyond tamoxifen

Breast Cancer Res.

Chemoprevention of breast cancer

Cancer Treat. Res.

Breast cancer prevention trials

Curr. Oncol. Rep.

Steroid hormone binding and hormone receptors

The signals and molecular pathways involved in human menstruation a unique process of tissue destruction and remodelling

Mol. Hum. Reprod.

Physiological action of progesterone in target tissues

Endocr. Rev.

Apoptosis, proliferation, and sex hormone receptors in superficial parts of human endometrium at the end of the secretory phase

J. Clin. Endocrinol. Metab.

The endocrinology and developmental biology of the prostate

Endocr. Rev.

Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer

Prostate

Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer

New Engl. J. Med.

Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence

Clin. Cancer Res.

Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function

Mol. Endocrinol.

Pharmacological manipulation of granulocyte apoptosis: potential therapeutic targets

Trends Pharmacol. Sci.

Glucocorticoids in T cell development and function

Annu. Rev. Immunol.

Apoptosis in Xenopus tadpole tail muscles involves Bax-dependent pathways

FASEB J.

Thyroid hormones and brain development

Eur. J. Endocrinol.

An unliganded thyroid hormone receptor causes severe neurological dysfunction

Proc. Natl. Acad. Sci. U. S. A.

Role of retinoids in differentiation and carcinogenesis

Cancer Res.

Embryonic retinoic acid synthesis is essential for early mouse post-implantation development

Nat. Genet.

Retinoids and cancer in experimental animals

Review
Nuclear receptors in cell life and death