Inhibition of MITF transcriptional activity independent of targeting p300/CBP coactivators

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Abstract

Summary

Microphthalmia-associated transcription factor (MITF) activates the expression of melanocyte-specific markers and promotes the survival of embryonic, adult and malignant melanocytes. Although numerous MITF-dependent downstream genes have been identified, the mechanisms by which the MITF activity is coregulated remain elusive. Here we used a non-melanocytic cell line U2-OS as a model in which MITF evokes transcription of a paradigmatic MITF target tyrosinase and show that the adenoviral E1A protein represses the MITF-driven transcription in these cells. The E1A CR1 domain (which alone is insufficient to bind p300) was sufficient for repression, while the N-terminus, through which E1A binds the p300/CBP proteins and other coactivators, was unable to repress. Correspondingly, CR1 inhibited colony formation of MITF-positive, but not MITF-negative, melanoma cells. The repression by CR1 was largely independent of the PCAF-binding motif, previously recognized to be necessary for suppression of muscle-specific enhancer. Interestingly, CR1 conferred transcriptional competence to the MITF-CR1 chimera in which the MITF portion was rendered transcription-deficient. Moreover, MITF mutants defective in binding to p300/CBP in vivo still activated transcription, further supporting a p300/CBP-independent coactivation of MITF targets. MITF is amplified in a subset of melanomas and is thought to be required for sustained proliferation of malignant melanocytes. Our results suggest that understanding how CR1 represses Mitf activity may reveal a route to melanoma therapy.

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