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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)