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
-
- Animals
- Cell Differentiation/genetics*
- DEAD-box RNA Helicases/genetics
- DEAD-box RNA Helicases/metabolism*
- Gene Expression Regulation, Developmental
- Humans
- Melanocytes/cytology*
- Melanoma/genetics
- Melanoma/metabolism*
- Microphthalmia-Associated Transcription Factor/genetics
- Mutation
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism*
- Protein Tyrosine Phosphatases/genetics
- Protein Tyrosine Phosphatases/metabolism*
- Stem Cells/metabolism
- Zebrafish/metabolism
- Zebrafish Proteins/metabolism
- PubMed
- 32652076 Full text @ Dev. Cell
Citation
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. (2020) PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation. Developmental Cell. 54(3):317-332.e9.
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