Morphometric studies of the localization of the glucocorticoid receptor in mammalian cells and of glucocorticoid hormone-induced effects.

Akner, Gunnar; Wikström, Ann Charlotte; Mossberg, Kurt A.; Sundqvist, K. G.; Gustafsson, Jan‐Åke

doi:10.1177/42.5.8157935

Cited by 25 publications

(14 citation statements)

References 7 publications

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“…A related possibility is that diminished translocation of gsmGR reflects impaired unmasking of the major NLS [30]. The NLS is normally masked by the non-liganded LBD, and unmasking is thought to be induced by GR ligand binding [9,31].…”

Section: Discussionmentioning

confidence: 97%

Mutations in squirrel monkey glucocorticoid receptor impair nuclear translocation

Her¹,

Patel²,

Schatzberg³

et al. 2005

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Discussionmentioning

confidence: 97%

Mutations in squirrel monkey glucocorticoid receptor impair nuclear translocation

Her¹,

Patel²,

Schatzberg³

et al. 2005

The Journal of Steroid Biochemistry and Molecular Biology

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“…Although we find tetraploid cells following GR loss (Movie S3), our data suggest that the majority of GR knockdown cells either progress through mitosis with errors or die in mitosis. GR localizes to centrosomes in both interphase and mitotic cells (36), making a possible role for GR in controlling centrosome number in S-phase. However, multipolarity occurs after normal bipolarization of the spindle (Movies S4-S6), suggesting normal centrosome number at the onset of mitosis.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Matthews

Berry

Morgan

et al. 2015

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

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The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.glucocorticoid receptor | mitosis | aneuploidy | DNA damage | cancer G lucocorticoids (Gcs) act through the glucocorticoid receptor (GR), a member of the nuclear hormone receptor superfamily, and a ligand-activated transcription factor (1-4). The GR is ubiquitously expressed and regulates energy metabolism, immunity, and cell fate decisions. The quiescent GR resides in the cytoplasm in a complex with heat shock proteins and immunophilins, attached to the microtubule architecture of the cell in a heat shock protein 90-dependent manner (5). Ligand binding drives GR transformation, involving N-terminal phosphorylation on S203 and S211 and rapid translocation to the nucleus requiring attachment to dynein by heat shock protein 90, immunophilins, and dynamitin (6). Once in the nucleus, GR binds directly to DNA to regulate transcription, or tethers to other DNA-bound transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1), to regulate their function (7-10).In mitosis, GR is phosphorylated on both S203 and S211, but in a ligand-independent manner (11), and more comprehensive phosphoproteomic analyses identify the presence of multiple N-terminal GR phosphoforms in purified mitotic spindle fractions (12). Although altered GR function in mitosis has been shown (11, 13, 14), the kinases responsible and cellular consequences have not been defined. The role of G...

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“…Recently, video image processors and microphotometers have been used to quantitate the staining intensity of enzyme immunohistochemical reactions (Akner et al, 1994;Alford et al, 1994;Coventry et al, 1994;Verschure et al, 1994;Watanabe et al, 1991Watanabe et al, ,1993Watanabe et al, ,1994Dodge et al, 1993;Shimid et al, 1993;Carter et al, 1992;Dobado-Berrios et al, 1992;Kayser et al, 1991). When immunostaining intensity in a section is proportional to amount of an antigen in the section, antigen content in the section can be measured by quantitative immunohistochemical methods (Dobado-Berrios et al, 1992;Watanabe et al, 1991;Chu et al, 1989;Nibbering and van Furth, 1987).…”

Section: Introductionmentioning

confidence: 98%

Relationship between immunostaining intensity and antigen content in sections.

Watanabe

Asaka²,

Kanamura³

1996

J Histochem Cytochem.

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We studied the relationship between staining intensity of immunohistochemical reaction and antigen content in sections. Alpha-fetoprotein (AFP) and albumin in sections cut from livers of newborn, 5-, 10-, 20-, and 60-day-old rats were examined as examples. First, we compared average immunostaining intensity (sum of specific absorbance in pixel/number of pixels) measured by image processing (IP), with antigen content measured by immunochemical assay to determine whether the intensity is proportional to antigen content. The intensity of AFP was proportional to the antigen content, whereas that of albumin was not. Subsequently, the antigen preservation test was carried out to determine whether the intensity was decreased by fixation and, if so, which type of decrease (proportional or disproportionate) occurred. Thereafter, antigen content in the same portion in the same immunostained section was measured by the microphotometric (MP) method followed by the IP method, because the MP method gives a low average antigen content when a decrease in antibody binding occurs in sections, whereas the average antigen content measured by the IP method is unchanged. The intensity of AFP decreased primarily by a proportional decrease in antigenicity during fixation. However, the intensity of albumin decreased not only by a proportional decrease during fixation but also by a disproportionate reduction in antibody binding during immunostaining or before fixation. The results indicate that AFP content in sections is measurable by quantitative immunohistochemical methods, whereas albumin content is not.

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Morphometric studies of the localization of the glucocorticoid receptor in mammalian cells and of glucocorticoid hormone-induced effects.

Cited by 25 publications

References 7 publications

Mutations in squirrel monkey glucocorticoid receptor impair nuclear translocation

Mutations in squirrel monkey glucocorticoid receptor impair nuclear translocation

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Relationship between immunostaining intensity and antigen content in sections.

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