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Publications (2)14.51 Total impact

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    ABSTRACT: LRP16 gene has been characterized as an estrogen-responsive gene. One 1/2ERE/GC-rich site was previously identified to be indispensable for -676/-214 (region A) fragment within LRP16 regulatory region to confer E2 action. Here, we report that -213/-24 fragment (region B) has higher E2-responsiveness than that of region A in MCF-7 cells, but not in HeLa cells. Deletion and mutation analyses of region B showed that multiple GC-sites are involved in the E2-stimulated response and one 30-bp fragment (-213 to -184 bp) is essential for conferring maximum E2-responsiveness. Results from the cotransfection assays containing Sp1-siRNA revealed that Sp1 is required for the basal transcription activity and E2-responsiveness of both regions A and B. Northern blot analysis demonstrated that inhibition of Sp1 in MCF-7 cells not only decreased the basal expression of LRP16, but markedly impaired its upregulation by E2. Results from gel mobility shift assays exhibited the direct binding of Sp1 protein to the 28-bp fragment (-211 to -184 bp), which was enhanced by the ERalpha titer. Moreover, the functional interaction of ERalpha and Sp1 proteins in the presence of E2 at the GC-rich sites in region B was confirmed by chromatin immunoprecipitation (ChIP) assays. In general, these results demonstrate that GC-rich sites in the proximal promoter of LRP16 gene are sufficient for E2 activation of LRP16 and the -213/-184 fragment containing only one GC site is essential for the maximal induction in MCF-7 cells. We also provide a model for Sp1-dependent regulation of genes by E2 through GC-rich motifs.
    The Journal of Steroid Biochemistry and Molecular Biology 04/2008; 109(1-2):47-56. · 3.98 Impact Factor
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    ABSTRACT: LRP16 was previously identified as an estrogen-induced gene in breast cancer cells. The responsiveness of LRP16 to estrogen and its functional effects in endometrial cancer (EC) cells are still unclear. Here, we show that the mRNA level and promoter activity of the LRP16 gene were significantly increased by 17beta-estradiol (E2) in estrogen receptor alpha (ER alpha)-positive Ishikawa human EC cells. Although the growth rate of Ishikawa cells was not obviously affected by ectopic expression of LRP16, the results of a Transwell assay showed an approximate one-third increase of the invasive capacity of LRP16-overexpressing cells. As a result of molecular screening, we observed that the expression of E-cadherin, an essential adhesion molecule associated with tumor metastasis, was repressed by LRP16. Further promoter analyses demonstrated that LRP16 inhibited E-cadherin transactivation in a dose-dependent manner. However, the inhibition was abolished by estrogen deprivation, indicating that the downregulation of E-cadherin transcription by LRP16 requires ER alpha mediation. Chromatin immunoprecipitation analyses revealed that the binding of ER alpha to the E-cadherin promoter was antagonized by LRP16, suggesting that LRP16 could interfere with ER alpha-mediated transcription. These results suggest that the upregulation of LRP16 by estrogen could be involved in invasive growth by downregulating E-cadherin in human ECs.
    Cell Research 11/2007; 17(10):869-80. · 10.53 Impact Factor