Open AccessTransforming growth factor‐β‐stimulated clone‐22 is a negative‐feedback regulator of Ras / Raf signaling: Implications for tumorigenesis
Author(s) -
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
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02108.x
Subject(s) - anti apoptotic ras signalling cascade , carcinogenesis , downregulation and upregulation , signal transduction , biology , suppressor , microbiology and biotechnology , cancer research , regulator , mutant , mapk/erk pathway , genetics , cancer , gene
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)