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Titolo:
Nucleocytoplasmic shuttling of the thyroid hormone receptor alpha
Autore:
Bunn, CF; Neidig, JA; Freidinger, KE; Stankiewicz, TA; Weaver, BS; McGrew, J; Allison, LA;
Indirizzi:
Coll William & Mary, Dept Biol, Williamsburg, VA 23187 USA Coll William & Mary Williamsburg VA USA 23187 Williamsburg, VA 23187 USA Univ Canterbury, Dept Zool, Christchurch 8001, New Zealand Univ Canterbury Christchurch New Zealand 8001 stchurch 8001, New Zealand
Titolo Testata:
MOLECULAR ENDOCRINOLOGY
fascicolo: 4, volume: 15, anno: 2001,
pagine: 512 - 533
SICI:
0888-8809(200104)15:4<512:NSOTTH>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
C-ERB-A; NUCLEAR-LOCALIZATION SIGNALS; FLUORESCENT PROTEIN CHIMERA; LIVING CELLS; GLUCOCORTICOID RECEPTOR; V-ERBA; XENOPUS OOCYTES; IMPORTIN-BETA; DNA-BINDING; MINERALOCORTICOID RECEPTORS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
72
Recensione:
Indirizzi per estratti:
Indirizzo: Allison, LA Coll William & Mary, Dept Biol, POB 8795, Williamsburg, VA 23187 USA Coll William & Mary POB 8795 Williamsburg VA USA 23187 187 USA
Citazione:
C.F. Bunn et al., "Nucleocytoplasmic shuttling of the thyroid hormone receptor alpha", MOL ENDOCR, 15(4), 2001, pp. 512-533

Abstract

The thyroid hormone receptor alpha (TR alpha) exhibits a dual role as an activator or repressor of gene transcription in response to thyroid hormone (T-3). Our studies show that TRa, formerly thought to reside solely in the nucleus tightly bound to DNA, actually shuttles rapidly between the nucleusand cytoplasm. The finding that TR alpha shuttles reveals an additional checkpoint in receptor control of gene expression. Using Xenopus oocyte microinjection assays, we show that there are two coexisting mechanisms for nuclear entry of TR alpha. First, nuclear import of TR alpha (molecular mass 46kDa) was not sensitive to general inhibitors of signal-mediated transport,indicating that TR alpha can enter the oocyte nucleus by passive diffusion. Second, when TR alpha was tagged with glutathione-S-transferase, import of the fusion protein (molecular mass 73 kDa) was completely blocked by these inhibitors, demonstrating that an alternative, signal-mediated import pathway exists for TR alpha. Nuclear retention of TR alpha in oocytes is enhanced in the presence of T-3, suggesting that more intranuclear binding sitesare available for the ligand-bound receptor. Using mammalian cells, we show that shuttling of green fluorescent protein (GFP)-tagged and untagged TR alpha is inhibited in both chilled and energy-depleted cells, suggesting that there is an energy-requiring step in the nuclear retention/export process. Nuclear export of TR alpha is not blocked by leptomycin B, a specific inhibitor of the export receptor CRM1, indicating that TR alpha does not require the CRM1 pathway to exit the nucleus. Dominant negative mutants of TR with defects in DNA binding and transactivation accumulate in the cytoplasm at steady state, illustrating that even single amino acid changes in functional domains may alter the subcellular distribution of TR. In contrast to TR alpha, nuclear export of its oncogenic homolog v-ErbA is sensitive to leptomycin B, suggesting that the oncoprotein follows a CRM1-mediated export pathway. Acquisition of altered nuclear export capabilities may contribute to the oncogenic properties of v-ErbA.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/06/20 alle ore 15:57:37