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Increased proteolytic processing of full-length Gli2 transcription factor reduces the hedgehog pathway activity in vivo.

ABSTRACT: The proteolytic processing of Gli2 and Gli3 full-length transcription factors into repressors is a key step of the regulation in Hedgehog (Hh) signaling. The differential Gli2 and Gli3 processing is controlled by the processing determinant domain or PDD, but its significance is not clear. We generated a Gli2 mutant allele, Gli2(3PDD) , in which the Gli3PDD substitutes for the Gli2PDD. As expected, Gli2(3PDD) is processed more efficiently and at a different position as compared to Gli2, indicating that PDD also determines the extent and site of Gli2 and Gli3 processing in vivo. The increase in levels of the Gli2 repressor in Gli2(3PDD) mutant reduces the Hh pathway activity. Gli2(3PDD) processing is still regulated by Hh signaling. These results indicate that the proper balance between the Gli2 full-length activator and repressor is essential for Hh signaling.

SUBMITTER: Li J

PROVIDER: S-EPMC3071291 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Increased proteolytic processing of full-length Gli2 transcription factor reduces the hedgehog pathway activity in vivo.

Li Juan J Wang Chengbing C Pan Yong Y Bai Zengliang Z Wang Baolin B

Developmental dynamics : an official publication of the American Association of Anatomists 20110218 4

The proteolytic processing of Gli2 and Gli3 full-length transcription factors into repressors is a key step of the regulation in Hedgehog (Hh) signaling. The differential Gli2 and Gli3 processing is controlled by the processing determinant domain or PDD, but its significance is not clear. We generated a Gli2 mutant allele, Gli2(3PDD) , in which the Gli3PDD substitutes for the Gli2PDD. As expected, Gli2(3PDD) is processed more efficiently and at a different position as compared to Gli2, indicatin ...[more]

PMID: 21337666

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Project description:BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGFβ/SMAD (transforming growth factor-β/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naïve cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.

Dataset Information

Increased proteolytic processing of full-length Gli2 transcription factor reduces the hedgehog pathway activity in vivo.

Publications

Increased proteolytic processing of full-length Gli2 transcription factor reduces the hedgehog pathway activity in vivo.

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