Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression
| Autor: | Erwan Le Scolan, Alain Mauviel, Delphine Javelaud, Vasileia I. Alexaki, Léon C van Kempen, Kunxin Luo |
|---|---|
| Přispěvatelé: | Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Department of Molecular & Cell Biology [Berkeley], University of California [Berkeley], University of California-University of California, This work was supported by the Donation Henriette et Emile Goutière, Institut National du Cancer (INCa, PLBIO 08-0126 ), Cancéropôle Ile-de- France, INSERM, CNRS, Ligue Nationale Contre le Cancer (Comité des Yvelines), and Université Paris XI (to A.M.), and by funds from NIH RO1 CA101891 (to K.L.). V.I.A. was the recipient of a Cancéropôle Ile-de-France/ Région Ile-de-France post-doctoral fellowship., University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), BMC, Ed. |
| Jazyk: | angličtina |
| Předmět: |
Cancer Research
Skin Neoplasms Leupeptins Nude Skin Neoplasms/metabolism Smad Proteins SMAD Mice 0302 clinical medicine Transforming Growth Factor beta MESH: Up-Regulation MESH: Animals Neoplasm Metastasis Smad Proteins/metabolism Melanoma 0303 health sciences Tumor MESH: Proteasome Endopeptidase Complex Cyclin-Dependent Kinase Inhibitor p21/genetics Intracellular Signaling Peptides and Proteins lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health Up-Regulation DNA-Binding Proteins Intracellular Signaling Peptides and Proteins/metabolism Oncology 030220 oncology & carcinogenesis Gene Knockdown Techniques [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Molecular Medicine RNA Interference Proteasome Inhibitors Transforming Growth Factor beta/metabolism Cyclin-Dependent Kinase Inhibitor p21 Transcriptional Activation MESH: Cell Line Tumor MESH: Melanoma MESH: RNA Interference Mice Nude [SDV.CAN]Life Sciences [q-bio]/Cancer Biology lcsh:RC254-282 Cell Line MESH: Cyclin-Dependent Kinase Inhibitor p21 03 medical and health sciences Downregulation and upregulation [SDV.CAN] Life Sciences [q-bio]/Cancer Melanoma/metabolism Cell Line Tumor Proto-Oncogene Proteins MESH: Cell Proliferation MESH: Intracellular Signaling Peptides and Proteins [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] medicine MESH: Mice Nude Animals Humans Neoplasm Invasiveness Leupeptins/pharmacology Autocrine signalling MESH: Mice MESH: Transforming Growth Factor beta 030304 developmental biology Cell Proliferation MESH: Humans Cell growth Research MESH: Skin Neoplasms SKI protein MESH: Smad Proteins MESH: Leupeptins Transforming growth factor beta MESH: Neoplasm Invasiveness medicine.disease MESH: Neoplasm Metastasis MESH: Gene Knockdown Techniques MESH: Cell Line MESH: Proto-Oncogene Proteins Proto-Oncogene Proteins/genetics Cancer cell Cancer research biology.protein MESH: Transcriptional Activation human activities DNA-Binding Proteins/genetics Neoplasm Transplantation MESH: Neoplasm Transplantation MESH: DNA-Binding Proteins |
| Zdroj: | Molecular Cancer Molecular Cancer, BioMed Central, 2011, 10 (1), pp.2. ⟨10.1186/1476-4598-10-2⟩ Molecular Cancer, 2011, 10 (1), pp.2. ⟨10.1186/1476-4598-10-2⟩ Molecular Cancer, 10:2. BMC Molecular Cancer, Vol 10, Iss 1, p 2 (2011) |
| ISSN: | 1476-4598 |
| DOI: | 10.1186/1476-4598-10-2 |
| Popis: | Background SKI and SnoN proteins have been shown to inhibit TGF-β signaling, acting both as transcriptional co-repressors in the cell nucleus, and as sequestrators of SMAD proteins in the cytoplasm. TGF-β, on the other hand, induces rapid, proteasome-mediated, degradation of both proteins. How elevated SKI and SnoN protein levels co-exist with active autocrine TGF-β signaling in cancer cells is yet to be understood. Results In this study, we found elevated SKI and SnoN protein levels in a panel of melanoma cell lines, as compared to normal melanocytes. There was no correlation between SKI protein content and the capacity of melanoma cells to invade Matrigel™, to form subcutaneous tumors, or to metastasize to bone after intracardiac inoculation into nude mice. Nor did we find a correlation between SKI expression and histopathological staging of human melanoma. TGF-β induced a rapid and dose-dependent degradation of SKI protein, associated with SMAD3/4 specific transcriptional response and induction of pro-metastatic target genes, partially prevented by pharmacologic blockade of proteasome activity. SKI knockdown in 1205Lu melanoma cells did not alter their invasive capacity or transcriptional responses to TGF-β, and did not allow p21 expression in response to TGF-β or reveal any growth inhibitory activity of TGF-β. Conclusions Despite high expression in melanoma cells, the role of SKI in melanoma remains elusive: SKI does not efficiently interfere with the pro-oncogenic activities of TGF-β, unless stabilized by proteasome blockade. Its highly labile nature makes it an unlikely target for therapeutic intervention. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|