Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC-and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.
Histone deacetylase and Cullin3-REN KCTD11 ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation / Canettieri, G., DI MARCOTULLIO, L., Greco, A., Coni, S., Antonucci, L., Infante, P., Pietrosanti, L., DE SMAELE, E., Ferretti, E., Miele, E., Pelloni, M., Giuseppina De, S., Emilia Maria, P., Paola, G., Giorgi, A., Christian, S., Luigi, V., Carlo, P., Schinina', M.E., Screpanti, I., et al.. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - STAMPA. - 12:2(2010), pp. 132-U91. [10.1038/ncb2013]
Histone deacetylase and Cullin3-REN KCTD11 ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation
CANETTIERI, Gianluca;DI MARCOTULLIO, LUCIA;GRECO, Azzura;CONI, SONIA;ANTONUCCI, LAURA;INFANTE, PAOLA;PIETROSANTI, LAURA;DE SMAELE, Enrico;FERRETTI, ELISABETTA;MIELE, EVELINA;PELLONI, MARIANNA;GIORGI, ALESSANDRA;SCHININA', Maria Eugenia;SCREPANTI, Isabella;GULINO, Alberto
2010
Abstract
Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC-and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
