The responses to numerous stress signals are important for cellular growth and survival. The p53 tumor-suppressor protein is stabilized under stress conditions and induces transcription of several genes to regulate cell cycle and apoptosis. Regarding p53 protein accumulation, inhibition of proteasomal degradation of p53 protein, which is mainly mediated by Mdm2, has received much attention. Here, we demonstrate that regulation of translation initiation is also crucial for p53 protein accumulation. Furthermore, we report that heterogeneous nuclear ribonucleoprotein (hnRNP) Q binds to the 5 0 -untranslated region (UTR) of mouse p53 mRNA and regulates translation efficiency of p53 and apoptosis progression. We also suggest that changes in cytosolic hnRNP Q levels contribute to cell cycle-dependent translational differences in p53 mRNA.

Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive cancer with a poor prognosis and low patient survival. Because chemotherapy for advanced HNSCC is often ineffective, discovering new therapeutic targets that are important for HNSCC development and progression and elucidating their molecular mechanisms are required. In the present study, we describe the role of DRAK1 (death-associated protein kinase-related apoptosis-inducing kinase 1) as a novel negative regulator of the transforming growth factor-β (TGF-β) tumor suppressor signaling pathway for the first time in human HNSCC cells. DRAK1 was significantly overexpressed in primary human HNSCCs and in HNSCC cell lines. Through gain- and loss-of-function experiments, we demonstrated that the DRAK1 expression level regulated TGF-β1-induced transcriptional activity and expression of the tumor suppressor gene p21(Waf1/Cip1). DRAK1 depletion enhanced TGF-β1-induced growth inhibition in vitro and suppressed tumorigenicity in xenograft models in vivo. Mechanistically, DRAK1 was predominantly localized in the cytoplasm and bound to Smad3, thereby interrupting Smad3/Smad4 complex formation, which is the core process for the induction of tumor suppressor genes by TGF-β1. Thus, our findings suggest that cytoplasmic DRAK1 increases tumorigenic potential through inhibition of TGF-β1-mediated tumor suppressor activity in HNSCC cells and may be a potential therapeutic target for HNSCCs.