Transforming growth factor‐β‐stimulated clone‐22 is a negative‐feedback regulator of Ras / Raf signaling: Implications for tumorigenesis

• Published in: Cancer science 2012-01, Vol.103 (1), p.26-33
• Main Authors: Nakamura, Masaki, Kitaura, Jiro, Enomoto, Yutaka, Lu, Yang, Nishimura, Koutarou, Isobe, Masamichi, Ozaki, Katsutoshi, Komeno, Yukiko, Nakahara, Fumio, Oki, Toshihiko, Kume, Haruki, Homma, Yukio, Kitamura, Toshio
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2011.02108.x

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)