Nuclear Hormone Receptor Localization

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Nuclear Hormone Receptor Localization

• Megan Knoch

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(No Transcript)
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• Nuclear Localization Signal
• Protein movement into the nucleus
• Protein diffuses through nuclear membrane
• Protein is actively transported into nucleus
  requiring NLS
• NLS is a short sequence rich in arginines and
  lysines
• Receptor may have more than 1 NLS
• NLS may be masked in the inactivated state and
  exposed in the active state

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• Glucocorticoid Receptor
• Receptor located in cytosol when not bound to
  ligand
• NLS located in LBD and hinge region (aa 497-524)
  to a lesser extent
• After ligand stimulation, GR forms clusters
  within the nucleus
• Disruption of microtubules did not alter cluster
  formation
• However, clusters do correspond to activated
  target genes
• Mineralcorticoid receptors exhibit the same
  pattern of relocation
• Antagonists not only disrupt clusters but prevent
  them from forming quickly

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Glucocorticoid Receptor Signaling
SIGMA-ALDRICH
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Cultured cells expressing glucocorticoid
receptors after treatment with dexamethosone
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• Thyroid Receptor
• Localized within the nucleus
• Binds with DNA even without a ligand present
• Associates with co-repressors
• Suppresses some promoters dependent on TRE
• Also localized in cytoplasm
• TR mutants relocates to the cytoplasm and only
  move to the nucleus when bound to a hormone

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• Progesterone Receptor
• NLS located in hinge region (aa 638-642) and on
  the second zinc finger
• Progesterone receptor (PR)-A
• 165 amino acids shorter than the B form
• Localized in nucleus when not bound to ligand
• Progesterone receptor (PR)-B
• Localized in cytoplasm when not bound to ligand
• Tertiary conformation results in less effective
  NLS
• Also, unidentified export signal may explain
  localization
• More research needed to explain localization
  differences

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Cultured cells expressing progesterone receptor A
Cultured cells expressing progesterone receptor B
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• Estrogen Receptor
• NLS located in the hinge region (aa 256-303)
• ER-?
• Located strictly in the nucleus but not in the
  nucleolus
• Localization is affected by ligand binding
• Distributed in uterus and mammary glands
• Highly homologous to ER-ß, especially in the
  DNA-binding domain
• ER-ß
• Distributed in the ovary, testis and prostrate

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The nucleus of cultured cells expressing estrogen
receptors
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References Guiochon-Mantel, A., Milgrom, E.
Cytoplasmic-Nuclear Trafficking of Steroid
Hormone Receptors. Trends Endocrinol. Metab.
(4) 1993. p. 322-328. Hager, G.L., Lim, C.S.,
Elbi, C., Baumann, C.T. Trafficking of Nuclear
Receptors within Cells. J. of Steroid
Biochemistry and Molecular Biology (74) 2000.
p. 249-254. Kawata, M., Matsuda, K., Nishi, M.,
Ogawa, H., Ochiai, I. Intracellular Dynamics
of Steroid Hormone Receptor. Neuroscience
Research (40) 2001. p. 197-203.