Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells

Sánchez-Vega, Beatriz; Krett, Nancy L.; Rosen, Steven T.; Gandhi, Varsha

doi:10.1158/1535-7163.mct-06-0344

Cited by 37 publications

(34 citation statements)

References 47 publications

(33 reference statements)

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“…in a cell-and concentration-specific manner (26). In fact, alterations in the steroid response may be more associated with a change in the relative levels of multiple isoforms rather than the presence or absence of a specific isoform (22). In our current study, we show not only additional alternative splice isoforms exist, but also how these isoforms may be important contributors to the stress and steroid response in a dosedependent manner.…”

Section: Discussionmentioning

confidence: 52%

“…Expression of this isoform has been associated with steroid resistance in small cell lung cancer cells and in childhood acute lymphoblastic leukemia (18,20). The other splice variants, hGR-P and hGR-A, were identified in a glucocorticoid-resistant multiple myeloma cell line (17,21,22). Human GR-P retains intron G between exons 7 and 8, whereas hGR-A is missing exons 5, 6, and 7.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Steroid Response of a Human Glucocorticoid Receptor Splice Variant

Baker

Green

Chew

et al. 2012

Shock

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Glucocorticoids remain a recommended therapy in advanced septic shock despite the often unpredictable response, and our understanding of the mechanisms regulating the steroid and stress response remains limited. Since the initial sequencing of the human glucocorticoid receptor α and β gene (hGRα and hGRβ), only three additional splice variants have been identified--all of which have been postulated to contribute to steroid resistance. During a survey of 97 healthy humans' blood, we identified two novel hGR splice isoforms (hGR-S1 and hGR-S1(-349A) retaining intron H between exons 8 and 9. Human GR-S1(-349A) contained a base deletion causing an early termination and a truncated protein of 118 amino acids, whereas hGR-S1 had an early termination occurring within intron H and resulted in a 745-amino acid protein. Both isoforms had decreased transactivation potentials compared with hGRα when tested in the absence of exogenous steroids. However, after treating with exogenous steroids, dose-response studies showed hGR-S1(-349A) had a substantial augmentation in activity at higher concentrations of hydrocortisone and methylprednisolone when compared with hGRα, whereas hGR-S1 did not. Removal of the 3' untranslated region (3'UTR) of the hGR-S1(-349A) mRNA sequence resulted in a loss of the augmented response. The isoform hGR-S1(-349A) augments the response to steroids, and this significant response appears to be critically regulated by the 3'UTR. The identification and evaluation of these unique hGR isoforms helps further the understanding of the complex genetic regulation of the stress and steroid response.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Enhanced Steroid Response of a Human Glucocorticoid Receptor Splice Variant

Baker

Green

Chew

et al. 2012

Shock

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“…Silvestrol was also capable of increasing the sensitivity of JJN-3 and KMS-11 cells to DEX. Although the molecular basis of DEX resistance in the clinic is not completely understood, several studies indicate that a source of acquired resistance in leukemic cells is due to low or defective GR (33)(34)(35)(36). In addition, long-term DEX treatment can lead to acquired resistance through mechanisms that may involve epigenetic events.…”

Section: Discussionmentioning

confidence: 99%

Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma

Robert¹,

Roman²,

Bramoullé

et al. 2014

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

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Enhanced protein synthesis capacity is associated with increased tumor cell survival, proliferation, and resistance to chemotherapy. Cancers like multiple myeloma (MM), which display elevated activity in key translation regulatory nodes, such as the PI3K/ mammalian target of rapamycin and MYC-eukaryotic initiation factor (eIF) 4E pathways, are predicted to be particularly sensitive to therapeutic strategies that target this process. To identify novel vulnerabilities in MM, we undertook a focused RNAi screen in which components of the translation apparatus were targeted. Our screen was designed to identify synthetic lethal relationships between translation factors or regulators and dexamethasone (DEX), a corticosteroid used as frontline therapy in this disease. We find that suppression of all three subunits of the eIF4F cap-binding complex synergizes with DEX in MM to induce cell death. Using a suite of small molecules that target various activities of eIF4F, we observed that cell survival and DEX resistance are attenuated upon eIF4F inhibition in MM cell lines and primary human samples. Levels of MYC and myeloid cell leukemia 1, two known eIF4F-responsive transcripts and key survival factors in MM, were reduced upon eIF4F inhibition, and their independent suppression also synergized with DEX. Inhibition of eIF4F in MM exerts pleotropic effects unraveling a unique therapeutic opportunity.silvestrol | hippuristanol | eIF4A | RNAi screening

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“…16,17 Thus, we stably expressed wild-type GR-␣ in MM1R cells ( Figure 1, MM1R-WT-GR) through lentiviral infection and compared them with empty vector lentivirus-infected MM1R cells (MM1R-EV, empty vector) and dexamethasone-sensitive MM1S cells. As previously published 18 and confirmed in Figure 1A, the resistant MM1R cell line (MM1R-EV in Figure 1A) has lost the expression of both GR-␣ and -␤ isoforms as the anti-GR antibody recognizes the 2 isoforms in MM1S cells.…”

Section: Ectopic Expression Of Wild-type Gr In Mm1r Cells Reestablishmentioning

confidence: 99%

Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors

Sharma

Lichtenstein

2008

Blood

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The mechanism by which the glucocorticoid (GC) dexamethasone induces apoptosis in multiple myeloma (MM) cells is unknown, although previous work suggests that either transactivation through the glucocorticoid response element (GRE), transrepression of NF-B, phosphorylation of RAFTK (Pyk2), or induction of Bim is important. We studied this question by ectopically expressing mutant glucocorticoid receptors (GRs) in the dexamethasone-resistant MM1R cell line, which has lost its GR. Lentiviral-mediated reexpression of wild-type GR restored GRE transactivation, NF-B transrepression, RAFTK phosphorylation, Bim induction, and dexamethasone-induced apoptosis. We then reexpressed 4 GR mutants, each possessing various molecular effects, into MM1R cells. A perfect correlation was present between induction of GRE transactivation and induction of apoptosis. In contrast, NF-B transrepression and RAFTK phosphorylation were not required for apoptosis. Although not required for dexamethasone-mediated apoptosis, NF-B inhibition achieved by gene transfer suggested that NF-B transrepression could contribute to apoptosis in dexamethasone-treated cells. Dexamethasone treatment of MM1R cells expressing a mutant incapable of inducing apoptosis successfully resulted in RAFTK (Pyk2) phosphorylation and Bim induction indicating the latter GR-mediated events were not sufficient to induce apoptosis. MM1R cells expressing mutant GRs will be helpful in defining the molecular mechanisms of dexamethasoneinduced apoptosis of myeloma cells.

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Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells

Cited by 37 publications

References 47 publications

Enhanced Steroid Response of a Human Glucocorticoid Receptor Splice Variant

Enhanced Steroid Response of a Human Glucocorticoid Receptor Splice Variant

Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma

Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors

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