Cancer science, 2012-01, Vol.103 (1), p.26-33
2012
Details
- Autor(en) / Beteiligte
- Titel
- Transforming growth factor‐β‐stimulated clone‐22 is a negative‐feedback regulator of Ras / Raf signaling: Implications for tumorigenesis
- Ist Teil von
- Cancer science, 2012-01, Vol.103 (1), p.26-33
- Ort / Verlag
- Oxford, UK: Blackwell Publishing Ltd
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Wiley Online Library - AutoHoldings Journals
- Beschreibungen/Notizen
- Transforming growth factor‐β (TGF‐β)‐stimulated clone‐22 (TSC‐22), also called TSC22D1‐2, is a putative tumor suppressor. We previously identified TSC‐22 downstream of an active mutant of fms‐like tyrosine kinase‐3 (Flt3). Here, we show that TSC‐22 works as a tumor suppressor through inhibiting Ras/Raf signaling. Notably, TSC‐22 was upregulated by Ras/Raf activation, whereas its upregulation was inhibited by concurrent STAT5 activation. Although TSC‐22 was normally retained in the cytoplasm by its nuclear export signal (NES), Ras/Raf activation caused nuclear translocation of TSC‐22, but not TSC22D1‐1. Unlike glucocorticoid‐induced leucine zipper (GILZ/TSC22D3‐2) previously characterized as a negative regulator of Ras/Raf signaling, TSC‐22 failed to interact physically with Ras/Raf. Importantly, transduction with TSC‐22, but not TSC22D1‐1, suppressed the growth, transformation and tumorigenesis of NIH3T3 cells expressing oncogenic H‐Ras: this suppression was enhanced by transduction with a TSC‐22 mutant lacking NES that had accumulated in the nucleus. Collectively, upregulation and nuclear translocation of TSC‐22 played an important role in the feedback suppression of Ras/Raf signaling. Consistently, TSC22D1‐deficient mice were susceptible to tumorigenesis in a mouse model of chemically‐induced liver tumors bearing active mutations of Ras/Raf. Thus, TSC‐22 negatively regulated Ras/Raf signaling through a mechanism different from GILZ, implicating TSC‐22 as a novel suppressor of oncogenic Ras/Raf‐induced tumors. (Cancer Sci 2012; 103: 26–33)
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1347-9032eISSN: 1349-7006DOI: 10.1111/j.1349-7006.2011.02108.xTitel-ID: cdi_proquest_miscellaneous_954637241
- Format
- –
- Schlagworte
- Amino acids, Animal models, Animals, Blotting, Western, Cancer, Cell growth, Cell Transformation, Neoplastic - pathology, Cells, Cultured, Cloning, Cytoplasm, Diethylnitrosamine - toxicity, Feedback, Gene Expression Regulation, Neoplastic, Growth factors, H-Ras protein, Immunoprecipitation, Kinases, Leucine zipper proteins, Leukemia, Liver, Liver Neoplasms, Experimental - chemically induced, Liver Neoplasms, Experimental - genetics, Liver Neoplasms, Experimental - pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutants, Mutation, NIH 3T3 Cells, Nuclear transport, Original, Plasmids, Precursor Cells, B-Lymphoid, Protein-tyrosine kinase, Proteins, raf Kinases - genetics, raf Kinases - metabolism, Raf protein, Ras protein, ras Proteins - genetics, ras Proteins - metabolism, Real-Time Polymerase Chain Reaction, Repressor Proteins - physiology, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger - genetics, Signal Transduction, Stat5 protein, STAT5 Transcription Factor - genetics, STAT5 Transcription Factor - metabolism, Transcription Factors - genetics, Transcription Factors - metabolism, Transformation, Transforming growth factor- beta, Transforming growth factor-b, Tumor suppressor genes, Tumorigenesis, Tumors, Up-regulation