Retinoic Acid Receptors β and γ Distinguish Retinoid Signals for Growth Inhibition and Neuritogenesis in Human Neuroblastoma Cells

Cheung, Belamy B.; Hocker, Jayne E.; Smith, Stewart A.; Reichert, Uwe; Norris, Murray D.; Haber, Michelle; Stewart, Bernard W.; Marshall, Glenn M.

doi:10.1006/bbrc.1996.1804

Cited by 23 publications

(18 citation statements)

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“…In our previous studies of neuroblastoma cells overexpressing RARb, we had not observed spontaneous neuritic di erentiation (Cheung et al, 1996), or an increased proportion of necrotic or apoptotic cells (data not shown). This suggested that overexpression of RARb may have in¯uenced the growth properties of neuroblastoma cells through an e ect on cell cycle Figure 3 Growth of control and RARb transfectants between 4 and 6 weeks after being removed from retinoid.…”

Section: Rarb Overexpression a Ects Cell Cycle Regulation In Neuroblamentioning

confidence: 58%

“…The observation that neural crest-derived tissues are a frequent target for the embryologic e ects of both retinoid excess and de®ciency in utero (MorrisKay, 1991) has suggested the theory that endogenous retinoids may be required for some aspects of normal neural crest development. It is probable that all of our in vitro experiments were performed in the presence of very low concentrations of retinoid ligand, since the RARb transfectants were always cultured in fetal calf serum, thus suggesting that overexpressed RARb enhances the sensitivity of neuroblastoma cells to low concentrations of retinoid ligand (Cheung et al, 1996). We have been unable to maintain any neuroblastoma cell lines in elemental, serum-free media to address the question of whether RARb can act in a ligandindependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Untreated neuroblastoma cells express high levels of RARa, low levels of RARg, and barely detectable levels of RARb, while retinoid treatment induces RARb expression some 40-fold and RARa expression by fourfold (Clagett-Dame et al, 1993;Marshall et al, 1994;Wuarin et al, 1994). We have previously shown, in comparative studies of neuroblastoma cells transfected with each of the three RAR subtypes, that only RARb transfectants demonstrated enhanced retinoid sensitivity and growth inhibition in the absence of added retinoid (Cheung et al, 1996). In the present study, we examined the relationship between the level of RAR subtype expression in primary neuroblastoma tumor tissue and patient prognosis, and found a strong correlation between high RARb expression and favorable prognosis.…”

Section: Introductionmentioning

confidence: 91%

“…We next sought to determine possible mechanisms for the prognostic e ect of high-level RARb expression in neuroblastoma tumor tissue, by extending our analyses of neuroblastoma cells transfected with an RARb expression vector (Cheung et al, 1996). The wellrecognized capacity of neuroblastoma tumors for spontaneous regression and di erentiation suggested that endogenous RARb expression in tumor tissue may be responsible for converting a temporary retinoid di erentiation signal, to an irreversible cellular di erentiation response.…”

Section: Rarb Transfectants Exhibit Irreversible Retinoid-induced Gromentioning

confidence: 99%

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Favorable prognostic significance of high-level retinoic acid receptor β expression in neuroblastoma mediated by effects on cell cycle regulation

et al. 1998

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We have previously shown that ectopic overexpression of retinoic acid receptor (RAR) subtypes a, b and g in human neuroblastoma cells had di erent e ects on growth and retinoid sensitivity. Only overexpressed RARb induced profound growth inhibition in the absence of additional retinoid, and increased retinoid sensitivity. In this study, we measured mRNA expression levels of RARa, b, and g in 50 primary neuroblastoma tumor samples, and found a strong correlation between favorable patient prognosis and high-level RARb expression. Human neuroblastoma cells transfected with a vector expressing RARb demonstrated irreversible growth arrest following a 1 week exposure to all-transretinoic acid, whereas control cells continued to proliferate. In the absence of additional retinoid, RARb transfectants demonstrated a higher proportion of cells in the G 0 /G 1 phase of the cell cycle, increased p21 WAF1/CIP1 expression and speci®c binding to a retinoic acid response element. These were changes which we also observed in control neuroblastoma cells following retinoid treatment. Our data indicate that RARb is an important factor mediating the growth inhibitory e ects of retinoids in neuroblastoma cells. The favorable e ect of high-level RARb expression on prognosis in primary tumor tissue may occur through RARb e ects on p21 expression and consequent G 0 /G 1 cell cycle arrest.

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Section: Rarb Overexpression a Ects Cell Cycle Regulation In Neuroblamentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Rarb Transfectants Exhibit Irreversible Retinoid-induced Gromentioning

confidence: 99%

See 2 more Smart Citations

Favorable prognostic significance of high-level retinoic acid receptor β expression in neuroblastoma mediated by effects on cell cycle regulation

et al. 1998

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“…RARb is expressed at a very low level, but is strongly induced by treatment with RA (Lovat et al, 1993;Redfern et al, 1994;Carpentier et al, 1997). In neuroblastoma cells transfected with RARs, only RARb transfectants exhibited marked growth inhibition and neuritogenic e ects (Cheung et al, 1996). Therefore, the induction of RARb is thought to play an important role in the morphological di erentiation as well as in the arrest of neuroblastoma cell growth.…”

Section: Introductionmentioning

confidence: 99%

Differentiation of neuroblastoma cells by phorbol esters and insulin-like growth factor 1 is associated with induction of retinoic acid receptor β gene expression

Pérez-Juste

Aranda

1999

Oncogene

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The retinoic acid (RA) receptor b isoform (RARb) plays an important role in RA-induced di erentiation of human neuroblastoma. In this study we show that insulin-like growth factor 1 (IGF-1) and tetradecanoyl phorbol acetate (TPA) induce RARb gene expression in neuroblastoma SH-SY5Y cells. IGF-1 and TPA caused a marked induction of RARb2 promoter activity and had a synergistic e ect with RA that also upregulates transcription. The e ect of RA is mediated by two RA responsive elements (RAREs), whereas the IGF-1 and TPA actions are independent of the RAREs and map to sequences that overlap the TATA box. These results suggest that the signaling pathways stimulated by TPA and IGF-1 could modify the components assembled at the core RARb2 promoter and activate transcription. Expression of Ras Val12 mimics the e ect of IGF-1 and TPA on the promoter, and a dominant negative Ras mutant abrogates activation. A dominant negative Raf also blocks activation showing that the Ras-Raf pathway mediates stimulation of the RARb2 promoter. Our results show that neuronal di erentiation induced by non-retinoid agents that activate Ras is accompanied by increased transcription of the RARb gene.

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Retinoic acid and nitric oxide promote cell proliferation and differentially induce neuronal differentiation in vitro in the cnidarian Renilla koellikeri

Estephane

Anctil

2010

Developmental Neurobiology

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Retinoic acid (RA) and nitric oxide (NO) are known to promote neuronal development in both vertebrates and invertebrates. Retinoic acid receptors appear to be present in cnidarians and NO plays various physiological roles in several cnidarians, but there is as yet no evidence that these agents have a role in neural development in this basal metazoan phylum. We used primary cultures of cells from the sea pansy Renilla koellikeri to investigate the involvement of these signaling molecules in cnidarian cell differentiation. We found that 9-cis RA induce cell proliferation in dose- and time-dependent manners in dishes coated with polylysine from the onset of culture. Cells in cultures exposed to RA in dishes devoid of polylysine were observed to differentiate into epithelium-associated cells, including sensory cells, without net gain in cell density. NO donors also induce cell proliferation in polylysine-coated dishes, but induce neuronal differentiation and neurite outgrowth in uncoated dishes. No other cell type undergoes differentiation in the presence of NO. These observations suggest that in the sea pansy (1) cell adhesion promotes proliferation without morphogenesis and this proliferation is modulated positively by 9-cis RA and NO, (2) 9-cis RA and NO differentially induce neuronal differentiation in nonadherent cells while repressing proliferation, and (3) the involvement of RA and NO in neuronal differentiation appeared early during the evolutionary emergence of nervous systems.

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Retinoic Acid Receptors β and γ Distinguish Retinoid Signals for Growth Inhibition and Neuritogenesis in Human Neuroblastoma Cells

Cited by 23 publications

References 0 publications

Favorable prognostic significance of high-level retinoic acid receptor β expression in neuroblastoma mediated by effects on cell cycle regulation

Favorable prognostic significance of high-level retinoic acid receptor β expression in neuroblastoma mediated by effects on cell cycle regulation

Differentiation of neuroblastoma cells by phorbol esters and insulin-like growth factor 1 is associated with induction of retinoic acid receptor β gene expression

Retinoic acid and nitric oxide promote cell proliferation and differentially induce neuronal differentiation in vitro in the cnidarian Renilla koellikeri

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