Retinoic Acid Receptors α and γ Mediate the Induction of “Tissue” Transglutaminase Activity and Apoptosis in Human Neuroblastoma Cells

Melino, Gerry; Draoui, Muriel; Bellincampi, Lorenza; Bernassola, Francesca; Bernardini, Sergio; Piacentini, Mauro; Reichert, Uwe; Cohen, Paul A.

doi:10.1006/excr.1997.3656

Cited by 49 publications

(34 citation statements)

References 29 publications

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“…Alternatively, the morphological effects after ligand-activation of overexpressed RARg may indicate a transition to a cell phenotype where apoptosis is a consequence of retinoic acid treatment, as has been reported for S-type neuroblastoma cells. 14 In contrast to recent results for squamous carcinoma cells, 15 RARg overexpression did not significantly affect fenretinide-induced apoptosis, and this suggests that RARg activation by fenretinide does not have a major role in apoptosis of neuroblastoma cells. One possibility is that, despite its minor contribution to RAR-RXR heterodimers in these cells, 7 RARb may be involved in apoptosis.…”

contrasting

confidence: 90%

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

et al. 2005

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contrasting

confidence: 90%

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

et al. 2005

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“…Furthermore, we also demonstrate that the process of differentiation towards a neuronal phenotype is accompanied by a sizeable decrease of proliferation, an effect that, on the basis of appropriate pharmacological controls, is clearly dependent on NO production. NO has been reported to inhibit the proliferation of various cell types by either cGMP-dependent or -independent mechanisms (Blachier et al, 1996;Buga et al, 1998;Chambaut-Guerin et al, 2000;Garg and Hassid, 1989;Garg and Hassid, 1990;Melino et al, 1997a). The use of a specific inhibitor of guanylate cyclase or of a cGMP analog allows us to state that, in SK-N-BE cells, the negative regulation of proliferation exerted by NO is primarily cGMP dependent.…”

Section: No Negatively Regulates Neural Proliferationmentioning

confidence: 99%

Nitric oxide negatively regulates proliferation and promotes neuronal differentiation through N-Myc downregulation

Ciani

Severi

Contestabile

et al. 2004

Journal of Cell Science

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Nitric oxide (NO) has been found to act as an important negative regulator of cell proliferation in several systems. We report here that NO negatively regulates proliferation of neuronal cell precursors and promotes their differentiation by downregulating the oncogene N-Myc. We have studied this regulatory function of NO in neuroblastoma cell lines (SK-N-BE) and in primary cerebellar granule cell cultures. In a neuronal NO synthase (nNOS) overexpressing neuroblastoma cell line exposed to the differentiative action of retinoic acid, NO slowed down proliferation and accelerated differentiation towards a neuronal phenotype. This effect was accompanied by a parallel decrease of N-Myc expression. Similar results could be obtained in parental SK-N-BE cells by providing an exogenous source of NO. Pharmacological controls demonstrated that NO's regulatory actions on cell proliferation and N-Myc expression were mediated by cGMP as an intermediate messenger. Furthermore, NO was found to modulate the transcriptional activity of N-Myc gene promoter by acting on the E2F regulatory region, possibly through the control of Rb phosphorylation state, that we found to be negatively regulated by NO. In cerebellar granule cell cultures, NOS inhibition increased the division rate of neuronal precursors, in parallel with augmented N-Myc expression. Because a high N-Myc expression level is essential for neuroblastoma progression as well as for proliferation of neuronal precursors, its negative regulation by NO highlights a novel physiopathological function of this important messenger molecule.

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“…In many of these systems ligands that activate particular subsets of RARs have proven to be particularly efficacious. Apoptosis of tracheal epithelial cells is preferentially induced by RARa agonists (Zhang et al, 1995), apoptosis of thymic lymphocytes responds best to RARg ligands (Szondy et al, 1997), co-stimulation of RARa and RARg induces apoptosis in neuroblastoma cells (Melino et al, 1997), and ligand activation of RARb may play a particularly important role in limb teratogenesis (Soprano et al, 1994). We have recently shown that RXR ligands can also be very effective inducers of apoptosis in myeloid leukemia cells (Nagy et al, 1996b;Nagy et al, 1995).…”

Section: Retinoid Receptors and Apoptosismentioning

confidence: 99%

Retinoid-induced apoptosis in normal and neoplastic tissues

Thomázy²,

et al. 1998

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Vitamin A and its derivatives (collectively referred to as retinoids) are required for many fundamental life processes, including vision, reproduction, metabolism, cellular differentiation, hematopoesis, bone development, and pattern formation during embryogenesis. There is also considerable evidence to suggest that natural and synthetic retinoids have therapeutical effects due to their antiproliferative and apoptosis-inducing effectsin human diseases such ascancer. Therefore it is not surprising that a significant amount of research was dedicated to probe the molecular and cellular mechanisms of retinoid action during the past decade. One of the cellular mechanisms retinoids have been implicated in is the initiation and modulation of apoptosis in normal development and disease. This review provides a brief overview of the molecular basis of retinoid signaling, and focuses on the retinoid-regulation of apoptotic cell death and gene expression during normal development and in pathological conditions in vivo and in various tumor cell lines in vitro.Keywords: retinoic acid; retinoic acid receptor; RAR; RXR; apoptosis; tissue transglutaminase; gene expression Abbreviations: ATRA, All-trans retinoic acid; 9-cis RA, 9-cis retinoic acid; PG-J 2 , 15-deoxy-D 12,14 PGJ 2 ; RAR, retinoic acid receptor; RXR, retinoid X receptor; Tgase, tissue transglutaminase; SMRT, silencing mediator of retinoid and thyroid receptors; N-CoR, nuclear receptor corepressor; CREB, creb binding protein; HDAC-1, histone deacetylase-1 Retinoids are modulators of transcriptionThe retinoid's mechanism of action in both normal and pathological conditions has been the subject of more than a decade of intense research. The cloning and discovery of the retinoic acid receptor (RAR), which belongs to the superfamily of ligand-activated transcription factors (nuclear receptors) revolutionized our understanding as to how retinoids exert their pleiotropic effects (for reviews see Chambon (1996);Mangelsdorf et al (1994)). Members of the nuclear receptor superfamily mediate the biological effects of many hormones, vitamins and drugs (i.e. steroid hormones, thyroid hormones, vitamin D, prostaglandin-J 2 (PG-J 2 ) and drugs that activate peroxisomal proliferation). There are two families of retinoid receptors, Retinoid X Receptors (RXRs) that bind 9-cis retinoic acid (9-cis RA) and Retinoic Acid Receptors (RARs) that bind both 9-cis RA and all-trans retinoic acid (ATRA) (for reviews see Chambon 1996;Mangelsdorf et al, 1994)). Each of these receptor families includes at least three distinct genes, (RARa,b and g; RXRa,b and g) that through differential promoter usage and alternative splicing, give rise to a large number of distinct retinoid receptor proteins (for reviews see

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Retinoic Acid Receptors α and γ Mediate the Induction of “Tissue” Transglutaminase Activity and Apoptosis in Human Neuroblastoma Cells

Cited by 49 publications

References 29 publications

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

Nitric oxide negatively regulates proliferation and promotes neuronal differentiation through N-Myc downregulation

Retinoid-induced apoptosis in normal and neoplastic tissues

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