# Non-canonical transcriptional activation of MITF in pigment cells.

> **NIH AR K99** · MASSACHUSETTS GENERAL HOSPITAL · 2026 · $107,784

## Abstract

Project Summary
MITF, particularly the melanocyte-restricted m-MITF isoform, is a key transcription factor that regulates
melanocyte differentiation, survival, and pigmentation. Its expression is dynamically regulated by the MC1R
receptor through the PKA signaling pathway. For decades, it was thought that CREB1 was the PKA-controlled
transcription factor that drove m-MITF transcription. However, I have discovered that a non-canonical mechanism
activates m-MITF independent of CREB1 and its redundant paralogs. This mechanism requires the
transcriptional co-activator CRTC, which must be recruited to m-MITF promoter DNA through an unknown factor.
We propose here to define this non-canonical mechanism, discover its unknown regulators, and characterize the
precise molecular interactions required for m-MITF transcriptional activation. Specifically, we will 1) generate a
toolkit of mutant cell lines designed to perturb select events in PKA signaling and dissect the differences between
non-canonical and canonical regulation, 2) perform functional genomic screens to unveil new regulators of m-
MITF using cellular proliferation and transcriptional reporter readouts, and 3) investigate physical interactions
between identified regulators and the m-MITF promoter to develop a molecular model for the non-canonical
mechanism. As a feature of each of these aims, we will apply our findings to genetically modified, iPSC-derived
primary melanocytes and organotypic skin reconstitutions to address this mechanism's role in physiological
tissue pigmentation. This work will deepen our understanding of the molecular biology of pigmentation and give
insight into PKA signaling in other specialized cell types. It will lay the foundation for molecular approaches to
manipulate m-MITF in a melanocyte-specific manner for the chemoprevention and treatment of numerous sun-
and pigmentation-related conditions, including skin cancer and aging.

## Key facts

- **NIH application ID:** 11300448
- **Project number:** 1K99AR084551-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Charles Hank Adelmann
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** AR
- **Fiscal year:** 2026
- **Award amount:** $107,784
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11300448

## Citation

> US National Institutes of Health, RePORTER application 11300448, Non-canonical transcriptional activation of MITF in pigment cells. (1K99AR084551-01A1). Retrieved via AI Analytics 2026-07-10 from https://api.ai-analytics.org/grant/nih/11300448. Licensed CC0.

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