Abstract:
:The human progesterone receptor (PR) is a ligand-dependent transcription factor and two isoforms, (PRA and PRB), can be distinguished. PROGINS, a PR polymorphic variant, affects PRA and PRB and acts as a risk-modulating factor in several gynaecological disorders. Little is known about the functional consequences of this variant. Here, we characterise the properties of PROGINS with respect to transcription, mRNA maturation, protein activity and proliferation. PROGINS is characterised by a 320 bp PV/HS-1 Alu insertion in intron G and two point mutations, V660L in exon 4 and H770H (silent substitution) in exon 5. The Alu element contains a half oestrogen-response element/Sp1-binding site (Alu-ERE/Sp1), which acts as an in-cis intronic enhancer leading to increased transcription of the PROGINS allele in response to 17beta-oestradiol. Moreover, Alu insertions in the human genome are frequently methylated. Our data indicate that the PROGINS-Alu does not affect gene transcription due to DNA methylation. However, the Alu element reduced the stability of the PROGINS transcript compared with the CP allele and does not generate splice variants. The amino acid substitution (V600L) in exon 4 leads to differences in PR phosphorylation and degradation in the two PR variants upon ligand binding, most likely as a result of differences in the three-dimensional structures of the two PR variants. As a consequence, the PR-L660 (PROGINS) variant (1) displays decreased transactivation activity in a luciferase reporter system and (2) is less efficient in opposing cell proliferation in hamster ovarian cells expressing human PRA, when compared with the PR-V660 (most common variant). Taken together, our results indicate that the PROGINS variant of PR is less responsive to progestin compared with the most common PR because of (i) reduced amounts of gene transcript and (ii) decreased protein activity.
journal_name
J Mol Endocrinoljournal_title
Journal of molecular endocrinologyauthors
Romano A,Delvoux B,Fischer DC,Groothuis Pdoi
10.1677/jme.1.02170subject
Has Abstractpub_date
2007-02-01 00:00:00pages
331-50issue
1-2eissn
0952-5041issn
1479-6813pii
38/2/331journal_volume
38pub_type
杂志文章abstract::cDNA clones coding for rabbit prolactin were isolated from a pituitary library using a rat prolactin RNA probe. One cDNA contained 873 bases including the entire coding sequence of rabbit prolactin, its signal peptide and the 5' and 3' untranslated regions of 44 and 145 nucleotides respectively. The deduced amino acid...
journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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doi:10.1677/jme.0.0100115
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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journal_title:Journal of molecular endocrinology
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