Functional analysis of an alternatively spliced estrogen receptor lacking exon 4 isolated from MCF-7 breast cancer cells and meningioma tissue

Koehorst, S. G. A.; Cox, Joke J.; Donker, G.H.; Silva, S.Lopes da; Burbach, J. Peter H.; Thijssen, J. H. H.; Blankenstein, Marinus A.

doi:10.1016/0303-7207(94)90240-2

Cited by 55 publications

(18 citation statements)

References 22 publications

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“…Although greater cellular resolution is possible with in situ hybridization techniques, the finding of ER mRNA in the pyramidal cells vs. interneurons seems to depend on the DNA sequences to which the probes were made (Pelletier et al, 1988;Simerly et al, 1990;O'Keefe et al, 1995). Additionally, the presence of truncated forms of the ER mRNA (Skipper et al, 1993), which may be recognized by some probes and which do not generate functional protein (Pfeffer et al, 1993;Koehorst et al, 1994), may confound the interpretation of the in situ results. Recent work with a newly cloned ␤ form of the ER (Kuiper et al, 1996) has established the presence of ER␤ mRNA in brain (Kuiper et al, 1997).…”

Section: Discussionmentioning

confidence: 90%

Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats

Weiland

Orikasa

Hayashi³

et al. 1997

J. Comp. Neurol.

301

116

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Estrogen regulates the synaptic plasticity and physiology of the hippocampus as well as learning behaviors that are mediated by the hippocampus. The density of dendritic spines and synapses, the number of N-methyl-D-aspartate (NMDA) binding sites, the levels of NMDA receptor subunit NR1 protein, muscimol binding to the gamma-amino butyric acid (GABA)A receptor, and levels of glutamic acid decarboxylase message in the CA1 region of the hippocampus are altered with estrogen treatment. In addition, some of these parameters exhibit sex differences in their response to estrogen treatment. To establish that estrogen can have a direct effect on the hippocampus and to determine whether or not sex differences in estrogen responsiveness are due to sex differences in estrogen receptor (ER) levels, we used immunocytochemistry with the AS409 antibody to map the location of ER-immunoreactive (ER-ir) cells in the hippocampus of male and female rats. We found that (1) the ERs appear to be in interneurons rather than pyramidal or granule cell neurons, (2) ER-ir cells are located in greatest concentration in the hilus of the dentate gyrus and the stratum radiatum of the CA1 region, (3) the density of ER-ir cells exhibits a rostral to caudal gradient in the hilus and the CA1 regions, (4) there are no sex differences in either the number or immunostaining intensity of ER-ir cells in the hippocampus, (5) the ER levels are down-regulated by estrogen in both male and female rats, and (6) the mean intensity of staining for the ER-ir cells in the hippocampus is about 25% of that in the ER-ir cells of the hypothalamus. From this, we can conclude that estrogen can have a direct effect on hippocampal neurons and that any sex differences in estrogen responsiveness is due to something other than sex differences in ER levels or function in the hippocampus.

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Section: Discussionmentioning

confidence: 90%

Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats

Weiland

Orikasa

Hayashi³

et al. 1997

J. Comp. Neurol.

301

116

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“…In addition to the recently described ER isoform ER␤ (4), several variants of the ER␣ have been identified in human breast cancer (5-7) and tumor cell lines (7,8). These variants have contained point mutations (5,9), exon deletions (7,8,10), and C terminus truncations (6).…”

Section: Introductionmentioning

confidence: 99%

“…These variants have contained point mutations (5,9), exon deletions (7,8,10), and C terminus truncations (6). Some of these variants can have transcriptional effects (9,10).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation by a Naturally Occurring Truncated Rat Estrogen Receptor (ER), Truncated ER Product-1 (TERP-1)

Schreihofer

Resnick

Soh

et al. 1999

Molecular Endocrinology

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Truncated estrogen receptor product-1 (TERP-1) is a naturally occurring rat estrogen receptor (ER) variant transcribed from a unique start site and containing a unique 5'-untranslated region fused to exons 5-8 of ERalpha. TERP-1 is detected only in the pituitary, and TERP-1 mRNA levels are highly regulated during the estrous cycle, exceeding those of the full-length ERalpha on proestrus. These data suggest that TERP-1 may play a role in estrogen- regulated feedback in the pituitary. We examined the ability of TERP-1 to modulate gene transcription in transiently transfected ER-negative (Cos-1) and ER-positive pituitary (alphaT3 and GH3) cell lines. In Cos-1 cells transiently cotransfected with TERP-1 and either ERalpha or ERbeta, low levels of TERP-1 (ratios of < 1:1 with ER) enhanced transcription of model promoters containing estrogen response elements by an average of 3- to 4-fold above that seen with ER alone. At higher concentrations of TERP-1 (> 1:1 with ER) transcription was inhibited. TERP-1 also had a biphasic action on transcription in the alphaT3 and GH3 pituitary cell lines, although the stimulatory action was less pronounced. TERP-1 actions were dependent on ligand-activated ER as TERP-1 did not bind estradiol in transfected Cos-1 cells or in vitro, and estrogen antagonists prevented the stimulatory effects of TERP-1. Coimmunoprecipitation studies suggest that TERP-1 does not bind with high affinity to the full-length ERalpha. However, TERP-1 may compete with ER for binding sites of receptor cofactors because steroid receptor coactivator-1 (SRC-1) rescued the inhibitory actions of TERP-1. The ability of TERP-1 to both enhance and inhibit ER-dependent promoter activity suggests that TERP-1 may play a physiological role in estrogen feedback in the rat pituitary.

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“…It was demonstrated that based on the loss of particular exons, most of these mRNA variants code for proteins which have different biochemical and structural properties. Some variant proteins are unable to bind DNA or their ligand and thus are incapable of mediating estrogen signals (ERaD4, ERbD3) [12,13]. Other variants are not able to activate gene transcription, but exert dominant positive (ERaD5) [14,15] or negative effects on receptor function (ERaD7, ERbD5) [16,17].…”

Section: Introductionmentioning

confidence: 97%

Identification of novel transcript variants of estrogen receptor α, β and progesterone receptor gene in human endometrium

Springwald

Lattrich

Skrzypczak

et al. 2010

Endocr

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The human progesterone receptor (PR) and estrogen receptor genes (ESR1 and ESR2) are known to code for a multitude of transcript variants resulting from alternative splicing. Many of them are translated into nuclear receptor proteins with altered structure and function. Expression of these alternative estrogen and progesterone receptors modulates the cellular response to sexual steroid hormones. Recent studies also suggested their significance in development of hormone-dependent diseases like gynecological cancers. We report identification of 12 new transcript variations of the PR, ESR1, and ESR2 gene in human endometrium which result from differential exon-skipping. We succeeded in cloning of four new double or triple exon-deletion transcript variants of ERα, four single, double or triple exon-skipped mRNA isoforms of ERβ, and four new transcript variations of PR gene. Sequence analysis suggested that at least four of them, ERαΔ5/6, ERαΔ5/6/7, PRΔ7, and PRΔ6/7 are translated into receptor proteins which might exert ligand-independent effects on steroid hormone signalling. Comparison of pre- and post-menopausal endometrium revealed differential expression of PRΔ6/7, ERαΔ5/6/7, ERαΔ3/4/5, and ERβΔ1-0N. We also report differential expression of the exon-skipped isoforms in a panel of human cancer cell lines derived from the breast, ovary, and endometrium. Our identification of additional transcript variations further increases the complexity of steroid hormone receptor gene expression and signalling.

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Functional analysis of an alternatively spliced estrogen receptor lacking exon 4 isolated from MCF-7 breast cancer cells and meningioma tissue

Cited by 55 publications

References 22 publications

Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats

Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats

Transcriptional Regulation by a Naturally Occurring Truncated Rat Estrogen Receptor (ER), Truncated ER Product-1 (TERP-1)

Identification of novel transcript variants of estrogen receptor α, β and progesterone receptor gene in human endometrium

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