Genomic Structure of Human Adrenomedullin Gene

Ishimitsu, Toshihiko; Kojima, Miki; Kangawa, Kenji; Hino, Jun; Matsuoka, Hiroaki; Kitamura, Katsumasa; Eto, T.; Matsuo, Hirotoshi

doi:10.1006/bbrc.1994.2229

Cited by 196 publications

(121 citation statements)

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“…Of particular interest with respect to tamoxifen induced gene expression is the presence of two AP1 binding sites at position 71549 and 71801 respectively (Ishimitsu et al, 1994), as it has been demonstrated that tamoxifen is able to initiate gene transcription via an AP-1 site (Webb et al, 1995). In conclusion adrenomedullin has the potential to be a mediator for the proliferative and vascular e ects of tamoxifen on the uterus.…”

Section: Discussionmentioning

confidence: 98%

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

et al. 1998

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Tamoxifen is currently the most widely used drug for the treatment of breast cancer, but there now exists considerable evidence that tamoxifen can also induce endometrial hyperplasia in pre menopausal women. We have used PCR di erential display on primary human endometrial isolates in an attempt to identify genes induced by tamoxifen but not estrogen. Eight such di erentially expressed bands were cloned and sequenced, one of which was found to be the peptide adrenomedullin. We have shown that adrenomedullin is a novel growth factor for endothelial cells and is angiogenic in vivo in the chick chorioallantoic membrane assay. Immunohistochemical analysis of endometrial sections have shown that while macrophages in the endometrium express adrenomedullin at a low level, endometrial macrophages of women receiving tamoxifen strongly express adrenomedullin (P=0.008). We postulate that endometrial induction of the angiogenic factor adrenomedullin by tamoxifen is part of the mechanism by which tamoxifen results in endometrial hyperplasia.

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Section: Discussionmentioning

confidence: 98%

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

et al. 1998

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“…The mechanism by which TAM may increase aFGF, bFGF and ADM expression is presently unknown. However the presence of an AP-1 site in the promoters of aFGF, bFGF and ADM (Ishimitsu et al, 1994;Erdos et al, 1995;Payson et al, 1998), provides a possible mechanism for the TAM induction of these factors, as it has been demonstrated that TAM is able to initiate gene transcription via an AP-1 site (Webb et al, 1995). None of these factors have oestrogen response elements.…”

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

Tamoxifen induction of angiogenic factor expression in endometrium

et al. 2002

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Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre-and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre-but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen.

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“…PCR product was generated using primers a and b with pBS-hAM as the cDNA template that contains the entire 5 0 UTR of human AM mRNA. Uppercase and lowercase letters indicate sequence of 5 0 UTR or exon 1, and intron 1 (Ishimitsu et al, 1994), respectively. Translation signals are shown in bold.…”

Section: Resultsmentioning

confidence: 99%

“…The nucleotide sequences identified in the human AM cDNA are contained in four exons in the human gene for preproadrenomedullin (Ishimitsu et al, 1994). The analysis of AM gene sequence showed that the 65 basepair (bp) sequence (nt 31-95) is included in exon 1 coding for nt 1-134 of the 5 0 UTR (Figure 1), ruling out the possibility that the 65 bp region is an exon and can be deleted by alternative splicing events.…”

Section: Resultsmentioning

confidence: 99%

Identification of secondary structure in the 5′-untranslated region of the human adrenomedullin mRNA with implications for the regulation of mRNA translation

et al. 2006

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Adrenomedullin (AM) is a multifunctional regulatory peptide with important angiogenic and mitogenic properties. Here we identify a region of stable secondary structure in the 5 0 -untranslated region (5 0 UTR) of human AM mRNA. Reverse transcriptase-polymerase chain reaction of the 5 0 UTR consistently resulted, in addition to the product with the expected size of 155 base pair (bp), in a second product with an B65-bp deletion from the central region of the 5 0 UTR, suggesting the presence of a secondary structure. The presence of a stem-loop structure was confirmed by probing the 5 0 UTR with RNases with selectivity for single-or double-stranded RNA. We investigated the role of this stem-loop structure in expression of luciferase reporter gene in cultured cell lines. Reporter assays using a chimeric mRNA that combined luciferase and the 5 0 UTR of AM mRNA demonstrated a dramatic decrease of the reporter activity owing to a decreased translation, whereas the deletion of the stem-loop structure localized between nt þ 31 and þ 95 from the cap site led to the recovery of activity. Gel migration shift assays using cytosolic extracts from mammalian cell lines demonstrate a specific binding of a cytosolic protein to riboprobes containing the 5 0 UTR of AM but not to riboprobes either corresponding to other areas of the message or containing the 5 0 UTR but lacking the region of secondary structure. Although we conclude that the 5 0 UTR of the human AM mRNA can modulate the translation of AM mRNA in vivo, and that the predicted stem-loop structure is necessary for this inhibition, the functional consequences of the cis element-binding activity remain to be determined.

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Genomic Structure of Human Adrenomedullin Gene

Cited by 196 publications

References 0 publications

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium

Tamoxifen induction of angiogenic factor expression in endometrium

Identification of secondary structure in the 5′-untranslated region of the human adrenomedullin mRNA with implications for the regulation of mRNA translation

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