Retinoic acid receptors α and γ mediate the induction of 'tissue' transglutaminase activity and apoptosis in human neuroblastoma cells

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

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All-trans retinoic acid (RA) reduces human neuroblastoma growth by inducing either differentiation or apoptosis. The apoptotic program in these cells is regulated by RA and is paralleled by the transcriptional induction of 'tissue' transglutaminase (tTG). tTG is a protein cross-linking enzyme, which specifically accumulates in cells undergoing apoptosis in various in vivo and in vitro systems. In neuroblastoma cells, tTG is detected exclusively in the cells expressing the S-type phenotype and showing an increased apoptosis. The present study was undertaken to identify the retinoid receptors which are involved in the regulation of tTG and apoptosis as well as in the in vitro neuronal differentiation of the human SK-N-BE(2) neuroblastoma cell line. We have previously characterized the retinoid acid receptors expressed in this cell line. In the present study, by using synthetic retinoids selectively activating RAR/RXR isoforms, we have identified the RAR/RXR receptors involved in the induction of either apoptosis or differentiation. We have also studied the effect of the selective RA analogs on tTG activity. We observed that while RARα- and RARγ-selective retinoids alone were able to induce tTG activity, only the combined stimulation of both RARα and RARγ induced apoptosis. Conversely, several combinations of RAR/RXR closely mimicked the differentiation effects observed with all-trans retinoic acid. These results indicate that, at variance with differentiation, the induction of apoptosis in human SK-N- BE(2) neuroblastoma cells is under the specific control of RARα and RARγ. These data seem relevant for the reported ability of RARγ to suppress the clinically malignant tumor phenotype in patients.

Original languageEnglish
Pages (from-to)55-61
Number of pages7
JournalExperimental Cell Research
Issue number1
Publication statusPublished - Aug 25 1997

ASJC Scopus subject areas

  • Cell Biology


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