PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Johansson, Jeanette A.; Marie, Kerrie L.; Lu, Yuting; Brombin, Alessandro; Santoriello, Cristina; Zeng, Zhiqiang; Zich, Judith; Gautier, Philippe; Kriegsheim, Alex von; Brunsdon, Hannah; Wheeler, Ann P.; Dreger, Marcel; Houston, Douglas R.; Dooley, Christopher M.; Sims, Andrew H.; Busch-Nentwich, Elisabeth M; Zon, Leonard I.; Illingworth, Robert S.; Patton, E. Elizabeth

doi:10.1016/j.devcel.2020.06.013

Cited by 35 publications

(39 citation statements)

References 91 publications

(113 reference statements)

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“…In addition, DDX21 was found to regulate transcription in melanocyte stem cells (McSCs) in the hair follicle bulge to prevent differentiation into melanocytes. 76 There has been much debate recently about whether the cell at the origin of melanoma indeed represents a stem cell-like cell. In fact, the above-mentioned studies somewhat stand in contrast to reports claiming that instead of cells with stem cell features, fully differentiated melanocytes can give rise to melanoma.…”

Section: Significance Statementmentioning

confidence: 99%

“…Mechanistically, DHODH inhibition‐induced nucleotide stress has recently been linked to the RNA helicase DDX21, which senses nucleotide shortage in NCSCs as well as melanoma cells, upon which it stops transcriptional elongation 45 (Table 1). In addition, DDX21 was found to regulate transcription in melanocyte stem cells (McSCs) in the hair follicle bulge to prevent differentiation into melanocytes 76 …”

Section: Developmental Ncsc Genes Regulate Melanoma Growth and Homeosmentioning

confidence: 99%

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Reemergence of neural crest stem cell-like states in melanoma during disease progression and treatment

Diener

Sommer

2020

Stem Cells Translational Medicine

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Melanoma is the deadliest of all skin cancers due to its high metastatic potential. In recent years, advances in targeted therapy and immunotherapy have contributed to a remarkable progress in the treatment of metastatic disease. However, intrinsic or acquired resistance to such therapies remains a major obstacle in melanoma treatment. Melanoma disease progression, beginning from tumor initiation and growth to acquisition of invasive phenotypes and metastatic spread and acquisition of treatment resistance, has been associated with cellular dedifferentiation and the hijacking of gene regulatory networks reminiscent of the neural crest (NC)-the developmental structure which gives rise to melanocytes and hence melanoma. This review summarizes the experimental evidence for the involvement of NC stem cell (NCSC)-like cell states during melanoma progression and addresses novel approaches to combat the emergence of stemness characteristics that have shown to be linked with aggressive disease outcome and drug resistance.

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Section: Significance Statementmentioning

confidence: 99%

Section: Developmental Ncsc Genes Regulate Melanoma Growth and Homeosmentioning

confidence: 99%

Reemergence of neural crest stem cell-like states in melanoma during disease progression and treatment

Diener

Sommer

2020

Stem Cells Translational Medicine

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“…How to make the melanocytes cease to quiescent condition and reenter the cell cycle is the biggest challenge in melanocytes regeneration. It has been reported that the Kit receptor tyrosine kinase is essential for the regeneration of zebrafish larval melanocytes [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

5-Hydroxytryptamine (5-HT) Positively Regulates Pigmentation via Inducing Melanoblast Specification and Melanin Synthesis in Zebrafish Embryos

et al. 2020

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It has been reported that 5-hydroxytryptamine (5-HT) is related to melanogenesis in mice and melanoma cells. However, the underlying mechanisms of 5-HT in regulating pigmentation remains unknown. In this study, we aim to clarify the regulatory mechanism of 5-HT in the pigmentation of zebrafish embryos and B16F10 cells. Our results show that 5-HT induces the pigmentation of zebrafish embryos in a dosage-dependent manner at concentrations of 0.01–1 mM. Whole mount in situ hybridizations and qRT-PCR in zebrafish embryos indicate that the expression of neural crest cells marker gene sox10 is not changed in embryos treated with 5-HT compared to control group. The expression of mitfa, the marker gene of melanoblasts, is increased in the presence of 5-HT. Furthermore, 5-HT increased the expression of regeneration associated genes, namely kita, mitfa, and dct, after ablation of the melanogenic cells in zebrafish embryos. The experiments in B16F10 cells show that 5-HT promotes melanin synthesis by up-regulating the expression of key proteins MITF, TYR, TRP-1, and TRP-2. Especially, the small molecule inhibitor of PKA signaling, but not AKT and MAPK signaling, attenuates the up-regulation of MITF and TYR resulted from 5-HT induction in B16F10 cells. These results will help us to further understand the regulatory network of vertebrate pigmentation.

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“…PRL-3, in particular, has been identified as a potential cancer biomarker (1). PRL-3 expression was first identified as significantly upregulated in metastatic colorectal cancer, compared to primary lesions and normal tissue (2); since, PRL-3 has been implicated in progression and metastasis in gastric (3), ovarian (4), breast(5), brain (6), and prostate (7) cancers, melanoma (8) (9), and leukemias (10) (11). Experimental evidence indicates that PRL-3 expression increases proliferation, migration, and invasion of cancer cells in vitro (12) (13) (14) and enhances tumor growth and metastasis in mouse models (2) (15), while PRL-3 knockdown significantly suppresses tumor formation and spread in vivo (16).…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of nanobodies specifically targeting the oncogenic Phosphatase of Regenerating Liver-3 (PRL-3)

Smith

Min

Williamson

et al. 2020

Preprint

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Protein Tyrosine Phosphatase 4A3 (PTP4A3 or PRL-3) is an oncogenic dual specificity phosphatase that drives tumor metastasis, promotes cancer cell survival, has been linked to poor patient prognosis in a variety of tumor types. The mechanisms by which PRL-3 promotes tumor progression are not well understood, which is in part due to lack of tools to study this protein. The development of small molecule inhibitors that are specific to PRL-3 has proven difficult, as the PRL family is >80% homologous. As research tools, antibodies directed against PRL-3 have been more successful, although they are limited to certain assay types. To address this, we have designed, purified, and tested alpaca-derived PRL-3 single domain antibodies, or nanobodies. We have identified 7 unique nanobodies that bind to PRL-3 in ELISA with no activity towards PRL-1 and PRL-2. Anti-PRL-3 nanobodies immunoprecipitated PRL-3 from cell lysates and were used to define PLR-3 localization in human colon cancer cells in immunofluorescence cell staining experiments. These anti-PRL-3 nanobodies represent an important expansion of the tool set used for the study of PRL-3, and can be used to better define the role of PRL-3 in cancer progression while serving as a useful first step in the development of biologics to target PRL-3 in the clinic.

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PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Cited by 35 publications

References 91 publications

Reemergence of neural crest stem cell-like states in melanoma during disease progression and treatment

Reemergence of neural crest stem cell-like states in melanoma during disease progression and treatment

5-Hydroxytryptamine (5-HT) Positively Regulates Pigmentation via Inducing Melanoblast Specification and Melanin Synthesis in Zebrafish Embryos

Development and characterization of nanobodies specifically targeting the oncogenic Phosphatase of Regenerating Liver-3 (PRL-3)

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