Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chromosomal translocation t(15;17)(q22;q12) is a consistent feature of acute promyelocytic leukemia (APL) that results in the disruption of genes for the zinc finger transcription factor PML and the retinoic acid receptor alpha (RAR alpha). We have previously shown that PML is a growth suppressor and is able to suppress transformation of NIH/3T3 by activated neu oncogene. In the study presented here, the full-length PML cDNA was transfected into B104-1-1 cells (NIH/3T3 cells transformed by the activated neu oncogene) by retrovirally mediated gene transfer. We found that expression of PML could reverse phenotypes of B104-1-1 including morphology, contact-limiting properties, and growth rate in both transient-expression and stable transfectants. We also demonstrated that PML is able to suppress clonogenicity of B104-1-1 in soft agar assay and tumorigenicity in nude mice. These results strongly support our previous finding that PML is a transformation or growth suppressor. Our results further demonstrate that expression of PML in B104-1-1 cells has little effect on cell cycle distribution. Western blot analysis demonstrated that suppression of neu expression in B104-1-1 by PML was insignificant in the transient transfection experiment but significant in the PML stable transfectants. This study suggests that PML may suppress neu expression and block signaling events associated with activated neu. This study supports our hypothesis that disruption of the normal function of PML, a growth or transformation suppressor, is a critical event in APL leukomogenesis.
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PMID:PML suppresses oncogenic transformation of NIH/3T3 cells by activated neu. 775 92

The nonrandom chromosomal translocation t(15;17)(q22;q21) in acute promyelocytic leukemia (APL) juxtaposes the genes for retinoic acid receptor alpha (RAR alpha) and the putative zinc finger transcription factor PML. The breakpoint site encodes fusion protein PML-RAR alpha, which is able to form a heterodimer with PML. It was hypothesized that PML-RAR alpha is a dominant negative inhibitor of PML. Inactivation of PML function in APL may play a critical role in APL pathogenesis. Our results demonstrated that PML, but not PML-RAR alpha, is a growth suppressor. This is supported by the following findings: (i) PML suppressed anchorage-independent growth of APL-derived NB4 cells on soft agar and tumorigenicity in nude mice, (ii) PML suppressed the oncogenic transformation of rat embryo fibroblasts by cooperative oncogenes, and (iii) PML suppressed transformation of NIH 3T3 cells by the activated neu oncogene. Cotransfection of PML with PML-RAR alpha resulted in a significant reduction in PML's transformation suppressor function in vivo, indicating that the fusion protein can be a dominant negative inhibitor of PML function in APL cells. This observation was further supported by the finding that cotransfection of PML and PML-RAR alpha resulted in altered normal cellular localization of PML. Our results also demonstrated that PML, but not PML-RAR alpha, is a promoter-specific transcription suppressor. Therefore, we hypothesized that disruption of the PML gene, a growth or transformation suppressor, by the t(15;17) translocation in APL is one of the critical events in leukemogenesis.
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PMID:PML, a growth suppressor disrupted in acute promyelocytic leukemia. 793 3

In Xenopus, the primary neurons form in three domains either side of the midline in the posterior neurectoderm. At the late neurula stage there are approximately 120 primary sensory neurons on each side of the embryo. Co-injecting synthetic mRNA encoding retinoic acid receptor alpha (NR1B1) and retinoid X receptor beta (NR2B2) results in an increase in the number of primary neurons and this is further enhanced by the addition of retinoic acid indicating that elevated retinoid signalling promotes an increase in the number of cells undergoing primary neurogenesis. However, primary neurogenesis remains confined to the three domains that normally give rise to primary neurons indicating that not all regions of the neurectoderm respond equivalently to elevated retinoid signalling. The inhibition of retinoid signalling with a dominant negative retinoid receptor or treatment with citral, an inhibitor of retinoid metabolism, inhibits the formation of primary neurons. However, the lateral extent of the neurectoderm does not differ following these experimental manipulations suggesting that changes in primary neuron cell number, in response to changes in retinoid signalling, cannot be accounted for by significant gains or losses of neurectoderm. In addition, two lines of evidence are presented to suggest that retinoid signalling affects primary neurogenesis by acting directly on the neurectoderm. First, animal caps neuralized by noggin undergo primary neurogenesis in response to retinoid signalling and second primary neurogenesis is elevated in neural conjugates in which the ectodermal, but not the mesodermal, component has been co-injected with RAR/RXR mRNA.
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PMID:The control of Xenopus embryonic primary neurogenesis is mediated by retinoid signalling in the neurectoderm. 1070 32

The promyelocytic leukemia (PML) gene encodes a putative tumor suppressor gene involved in the control of apoptosis, which is fused to the retinoic acid receptor alpha (RARalpha) gene in the vast majority of acute promyelocytic leukemia (APL) patients as a consequence of chromosomal translocations. The PMLRARalpha oncoprotein is thought to antagonize the function of PML through its ability to heterodimerize with and delocalize PML from the nuclear body. In APL, this may be facilitated by the reduction to heterozygosity of the normal PML allele. To determine whether PML acts as a tumor suppressor in vivo and what the consequences of deregulated programmed cell death in leukemia and epithelial cancer pathogenesis are, we crossed PML(-/-) mice with human cathepsin G (hCG)-PMLRARalpha or mammary tumor virus (MMTV)/neu transgenic mice (TM), models of leukemia and breast cancer, respectively. The progressive reduction of the dose of PML resulted in a dramatic increase in the incidence of leukemia, and in an acceleration of leukemia onset in PMLRARalpha TM. By contrast, PML inactivation did not affect neu-induced tumorigenesis. In hemopoietic cells from PMLRARalpha TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vitamin D3 as well as in a marked survival advantage upon proapoptotic stimuli. These results demonstrate that: (a) PML acts in vivo as a tumor suppressor by rendering the cells resistant to proapoptotic and differentiating stimuli; (b) PML haploinsufficiency and the functional impairment of PML by PMLRARalpha are critical events in APL pathogenesis; and (c) aberrant control of programmed cell death plays a differential role in solid tumor and leukemia pathogenesis.
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PMID:Role of promyelocytic leukemia (PML) protein in tumor suppression. 1118 7

We hypothesized that specific activation of a single retinoic acid receptor-alpha (RARalpha), without direct and concurrent activation of RARbeta and gamma, will inhibit mammary tumor oncogenesis in murine models relevant to human cancer. A total of 50 uniparous mouse mammary tumor virus (MMTV)-neu and 50 nuliparous MMTV-wnt1 transgenic mice were treated with RARalpha agonist (retinobenzoic acid, Am580) that was added to the diet for 40 (neu) and 35 weeks (wnt1), respectively. Among the shared antitumor effects was the inhibition of epithelial hyperplasia, a significant increase (P<0.05) in tumor-free survival and a reduction in tumor incidence and in the growth of established tumors. In both models, the mechanisms responsible for these effects involved inhibition of proliferation and survival pathways, and induction of apoptosis. The treatment was more effective in the MMTV-wnt1 model in which Am580 also induced differentiation, in both in vivo and three-dimensional (3D) cultures. In these tumors Am580 inhibited the wnt pathway, measured by loss of nuclear beta-catenin, suggesting partial oncogene dependence of therapy. Am580 treatment increased RARbeta and lowered the level of RARgamma, an isotype whose expression we linked with tumor proliferation. The anticancer effect of RARalpha, together with the newly discovered pro-proliferative role of RARgamma, suggests that specific activation of RARalpha and inhibition of RARgamma might be effective in breast cancer therapy.
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PMID:Mechanism of inhibition of MMTV-neu and MMTV-wnt1 induced mammary oncogenesis by RARalpha agonist AM580. 2045 82