PUBLICATION
PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation
- Authors
- Johansson, J.A., Marie, K.L., Lu, Y., Brombin, A., Santoriello, C., Zeng, Z., Zich, J., Gautier, P., von Kriegsheim, A., Brunsdon, H., Wheeler, A.P., Dreger, M., Houston, D.R., Dooley, C.M., Sims, A.H., Busch-Nentwich, E.M., Zon, L.I., Illingworth, R.S., Patton, E.E.
- ID
- ZDB-PUB-200712-8
- Date
- 2020
- Source
- Developmental Cell 54(3): 317-332.e9 (Journal)
- Registered Authors
- Brombin, Alessandro, Busch-Nentwich, Elisabeth, Dooley, Christopher, Patton, E. Elizabeth, Santoriello, Cristina, Zeng, Zhiqiang, Zon, Leonard I.
- Keywords
- DDX21, MITF, PRL3, PTP4A3, melanocyte stem cell, melanoma, regeneration, small-molecule screen, transcription elongation, zebrafish
- MeSH Terms
-
- Humans
- Stem Cells/metabolism
- Animals
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism*
- PubMed
- 32652076 Full text @ Dev. Cell
Abstract
Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping