Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytopenias arising from hematopoietic abnormalities are a severe common complication contributing to early mortality in HIV/AIDS patients. The proto-oncogene c-mpl, identified as the thrombopoietin receptor is involved in multilineage differentiation of CD34+ hematopoietic progenitor cells. We have introduced the c-mpl gene into CD34+ cells via transduction of the lentivirus p156RRLsinPPTmPGK-CMPL-PRE. The lentiviral construct expresses c-mpl on approximately 90% of purified CD34+ cells. These transduced cells have then been reconstituted into human fetal thymus/liver implants in severe combined immunodeficient mice (SCID-hu Thy/Liv). The c-mpl expression on transduced CD34+ cells is not susceptible to downregulation due to the effects of HIV-1 infection. Reconstituted CD34+ cells transduced with control lentivirus, p156RRLsinPPTmPGK-EGFP-PRE, express EGFP at > 90%. Reconstituted c-mpl expressing SCID-hu implants show almost maximum rescue (approximately 90%) of myelopoiesis, erythropoiesis and megakaryopoiesis, during HIV-1 infection in vivo, at 6 weeks post-infection. We also show that the differentiated multi-lineage progeny colonies and thymocytes in mice reconstituted with the c-mpl transduced CD34+ cells, carry the HLA Class I loci phenotypes of these donor cells, in the implants of the recipient SCID-hu animals. We propose a gene therapeutic strategy, with c-mpl as the major genetic component, to address the morbidity and mortality resulting from cytopenias in HIV infected patients.
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PMID:Rescue of multi-lineage hematopoiesis during HIV-1 infection by human c-mpl gene transfer and reconstitution of CD34+ progenitor cells in vivo. 2023 1

Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment.
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PMID:Interaction between FGFR-2, STAT5, and progesterone receptors in breast cancer. 2146 42