PubMed · 5936982
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L Jordaan, M De Villiers, F Zaidy, W J Pepler. 1966. Primary aldosteronism.. https://doi.org/10.1002/bjs.1800530610
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Neuroblastoma (NB), a neural crest derived tumor in children, shows a characteristic pattern of dissemination that includes adrenal glands, local lymph nodes, bone, liver, skin, and bone marrow. We have reconstructed a similar metastatic pattern in SCID mice following tail vein injection of human NB cells. HTLA230, an NB cell line isolated from a patient with advanced disease, and its NGF receptor (trkA) expressing derivative (18-10) cells, consistently disseminated to the liver, the adrenal gland, and the bone marrow, but not the lungs. Metastases in the different organs showed a characteristic hemorrhagic histopathology, and tumors in the bone marrow presented as syncytia-like cell aggregates, typically seen in patients. Cell lines reestablished from 18-10 derived liver and bone marrow metastases maintained their cellular morphology, growth behavior, N-myc overexpression, trkA expression, and functionally responded to NGF treatment, leading to growth arrest and neurite outgrowth. Hence circulating human NB cells in SCID mice show a similar organ-specific metastatic potential as seen in patients, independent of trkA expression.
Rat pheochromocytoma PC12 cells are shown to express a single class of high affinity binding sites for bone morphogenetic protein (BMP)-2 (1,300 receptors/cell, Kd = 31.3 pM). Affinity cross-linking using radiolabeled BMP-2 demonstrated the presence of six components with apparent molecular masses of 170, 155, 105, 90, 80, and 70 kDa. BMP-2 induced morphological changes in PC12 cells with the concomitant expression of three neurofilament proteins. Thus, BMP-2 would appear to be another neurotrophic factor that, like nerve growth factor or basic fibroblast growth factor, stimulates the neuronal differentiation of PC12 cells. Unlike nerve growth factor and basic fibroblast growth factor, however, BMP-2 failed to induce the activation of either 41- and 43-kDa mitogen-activated protein (MAP) kinases or the MAP kinase/extracellular signal-regulated kinase kinase (MEK). Also, BMP-2 did not induce the expression of the c-fos gene in PC12 cells. Activin A was also capable of inducing the neuronal differentiation of PC12 cells without activating MAP kinases and MEK. These findings show a clear dissociation between the requirement for the activation of the MAP kinase cascade and the ability of BMP-2 and activin A to induce PC12 cell neuronal differentiation. In addition, these results suggest that the activation of MAP kinases and MEK is not an absolute requirement for PC12 cell differentiation.
GADD153, a ubiquitously expressed member of the CCAAT/enhancer-binding protein (C/EBP) family is induced by a wide variety of growth-arresting and DNA-damaging agents. Functionally, GADD153 has been postulated to act as a dominant-negative regulator of C/EBPs. Therefore we sought to gain evidence for interactions between GADD153 and other C/EBPs during cellular responses to stress. In this report we have demonstrated that treatment of rat pheochromocytoma PC12 cells with sodium arsenite leads to enhanced expression of C/EBP-beta and GADD153 (growth arrest and DNA damage inducible gene 153) but not other C/EBPs. Coimmunoprecipitation experiments provided evidence for the formation of endogenous GADD153-C/EBP-beta complexes in arsenite-treated cells. Additional experiments were performed to determine the role of such complexes in regulating GADD153 expression. Previous studies in our laboratory demonstrated that the GADD153 promoter contains a C/EBP binding site through which other C/EBPs interact to transactivate GADD153 expression in liver hepatoma cells. Here, we demonstrate that extracts prepared from arsenite-treated PC12 cells likewise show increased amounts of factors capable of binding to the GADD153-C/EBP site and that these complexes are comprised at least in part of C/EBP-beta. Forced expression of C/EBP-beta was found to be capable of transactivating the GADD153 promoter in PC12 cells cotransfected with plasmids expressing a GADD153 reporter gene and C/EBP-beta protein. However, overexpression of GADD153 inhibited the transactivation of the GADD153 promoter by C/EBP-beta. These findings provide evidence for an autoregulatory loop in which stress-induced GADD153 feeds back to attenuate GADD153 expression during the cellular response to stress.