RasGRP1 induces autophagy and transformation-associated changes in primary human keratinocytes
| Autor: | James Turkson, Dirk Geerts, Joe W. Ramos, Lauren L. Fonseca, Junfang Ji, Won Seok Yang |
|---|---|
| Přispěvatelé: | Medical Biology, Hematology laboratory |
| Rok vydání: | 2021 |
| Předmět: |
PBS
Phosphate Buffered Saline 0301 basic medicine Original article Cancer Research GFP Green Fluorescent Protein RasGRP1 Ras guanyl nucleotide-releasing protein 1 Cell EMT epithelial to mesenchymal transition Endogeny Vacuole Biology GTP Guanosine - 5′- Tri-Phosphate medicine.disease_cause lcsh:RC254-282 KEGG Kyoto Encyclopedia of Genes and Genomes LC3 microtubule-associated protein Light Chain 3 GEF guanine nucleotide exchange factor 03 medical and health sciences 0302 clinical medicine medicine PARP Poly ADP (Adenosine Diphosphate)-Ribose Polymerase Ras Rat Sarcoma (GTPase) HKn newborn-derived primary Human Keratinocytes Autophagy Wild type lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Epithelium In vitro LiF Li-Fraumeni Syndrome 030104 developmental biology medicine.anatomical_structure cSCC human cutaneous squamous cell carcinomas Oncology 030220 oncology & carcinogenesis GST Glutathione-S-Transferase ERK Extracellular Signa-Regulated Kinase Cancer research EGFR Epidermal Growth Factor Receptor Carcinogenesis DAG diacylglycerol FBS Fetal Bovine Serum |
| Zdroj: | Translational oncology, 14(1):100880. Neoplasia Press Translational Oncology Translational Oncology, Vol 14, Iss 1, Pp 100880-(2021) Fonseca, L L, Yang, W S, Geerts, D, Turkson, J, Ji, J & Ramos, J W 2021, ' RasGRP1 induces autophagy and transformation-associated changes in primary human keratinocytes ', Translational Oncology, vol. 14, no. 1, pp. 100880 . https://doi.org/10.1016/j.tranon.2020.100880 Translational Oncology, 14(1). Neoplasia Press |
| ISSN: | 1936-5233 |
| DOI: | 10.1016/j.tranon.2020.100880 |
| Popis: | Ras mutations are present in only a subset of sporadic human cutaneous squamous cell carcinomas (cSCC) even though Ras is activated in most. This suggests that other mechanisms of Ras activation play a role in the disease. The aberrant expression of RasGRP1, a guanyl nucleotide exchange factor for Ras, is critical for mouse cSCC development through its ability to increase Ras activity. However, the role of RasGRP1 in human keratinocyte carcinogenesis remains unknown. Here we report that RasGRP1 is significantly elevated in human cSCC and that high RasGRP1 expression in human primary keratinocytes triggered activation of endogenous Ras and significant morphological changes including cytoplasmic vacuole formation and growth arrest. Moreover, RasGRP1-expressing cells were autophagic as indicated by LC3-II increase and the formation of LC3 punctae. In an in vitro organotypic skin model, wild type keratinocytes generated a well-stratified epithelium, while RasGRP1-expressing cells failed to do so. Finally, RasGRP1 induced transformation-like changes in skin cells from Li-Fraumeni patients with inactivating p53 mutations, demonstrating the oncogenic potential of this protein. These results support a role for RasGRP1 in human epidermal keratinocyte carcinogenesis and might serve as an important new therapeutic target. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|