Hormone receptor nuclear localization

Picard D, Yamamoto KR (1987) Two signals mediate hormone dependent nuclear localization of the glucocorticoid receptor. EMBO J 6 3333... 

Understanding of the intracellular localization of steroid receptors has gone through a number of phases, beginning with the view that receptors translocated from cytoplasm to nucleus in the presence of hormone. Indeed, with the exception of thyroid hormone receptors, which are exclusively nuclear in location, cell fractionation studies have revealed that in the absence of hormone, steroid receptors are extracted in the soluble or cytosolic fraction. However, when steroid is present in the cell, many occupied receptors are retained by purified cell nuclei. Histological procedures, such as immunocytochemistry, have confirmed the largely nuclear localization of occupied receptors, but... 

The receptors for lipophilic signaling substances all belong to one protein superfamily. They are constructed in a modular fashion from domains with various lengths and functions. Starting from the N terminal, these are the regulatory domain, the DNA-binding domain, a nuclear localization sequence (see p. 228), and the hormone-binding domain (see p. 73D). 

The nuclear receptors are localized in the cytosol or nucleus. Due to their hpophihc nature the natural ligands of the nuclear receptors can cross the cell membrane in a passive marmer and bind the cognate receptor in the cell interior. Binding by hormones activates the transcription regulatory effect of the receptor. 

Cytoplasmically localized protein tyrosine phosphatases have a catalytic domain and other structural elements that specify the subcellular localization and association with effector molecules. These structural elements contain sequence signals for nuclear localization, for membrane association and for association with the cytoskeleton (see Fig. 8.16). The presence of SH2 domains suggests that these molecules might interact with signaling pathways involving growth hormones and receptor tyrosine kinases. 

Steroid hormones achieve their effects on target tissues through intracellular receptor proteins. According to recent views, oestrogen and progestin receptors are localized in the nuclear compartment of the cells, whereas glucocorticoid receptors may reside in both the cytoplasm and the nucleus. Determination of the intracellular localization of androgen receptors awaits the development of (monoclonal) antibodies which will enable immunohistochemical studies. The molecular aspects of the mechanism of action of steroid hormones will be covered in other chapters [1-3] in this volume. The present chapter deals with the characterization, assay and purification of steroid receptors. 

It is apparent from clinical and laboratory experiments and observation that the spread of breast cancer via the bloodstream occurs early in the course of the disease. This results in patients relapsing with systemic metastatic disease following local curative therapy. The likelihood of later development of metastatic disease is related to the size of the primary tumor, presence of lymph node involvement and number of nodes affected, and a number of additional pathologic prognostic factors, which include proliferative capacity, nuclear grade, hormone receptor status, and presence or absence of oncogenes and other protein products. Systemic adjuvant therapy is commonly... 

Based on the receptor activation mechanism, the nuclear receptors may be divided into two basic groups. In the first group (those including most of the steroid hormone receptors), the receptors can be localized in the nucleus or in the cytoplasm. The receptors of the other group (discussed in Section 4.7) are always localized in the nucleus. Representative ligands of these receptors are the derivatives of retinoic acid, the T3 hormone and VitD3. 

The exact role of PPIases is not yet fully understood. Their catalytic activity does not seem to be implicated in the assembly and composition of heterocomplexes, since these are insensitive to treatment with PPIase inhibitors. It has been proposed that PPIases might control the nuclear targeting of the receptor, a role consistent with the nuclear localization of hFKBP52 and hCyp40. It is noteworthy that the relative abundance of multidomain immunophilins may change in response to varied hormonal stimuli that upregulate the incorporation of TPR immunophilins into steroid receptor complexes [3,34],... 

Fig. 16.13. Steroid hormone receptors. A. Domains of the steroid hormone receptor. The transactivation domain (TAD) binds coactivators DNA-binding domain (DBD) binds to hormone response element in DNA ligand-binding domain (LBD) binds hormone NLS is the nuclear localization signal the dimerization sites are the portions of the protein involved in forming a dimer. The inhibitor binding site binds heat shock proteins and masks the nuclear localization signal. B. Transcriptional regulation by steroid hormone receptors. Additional abbreviations HSP, heat shock proteins GRE, glucocorticoid response element GIZ, glucocorticoid receptor.

Spindler, B. J, MacLeod, K. M., Ring, J., and Baxter, J. D. (1975). Thyroid hormone receptors binding characteristics and lack of hormonal dependenct for nuclear localization. J. Biol. Chem. 250 4113-4119. 

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