Self-aggregating TIAF1 in lung cancer progression

Translational Respiratory Medicine, Aug 2013

Recent studies have demonstrated that transforming growth factor beta (TGF-β1)-induced antiapoptotic factor (TIAF1) is able to form aggregates in the hippocampi of middle-aged normal individuals. The aggregating TIAF1 induces generation of amyloid beta (Aβ) for causing neurodegeneration. Intriguingly, TIAF1 aggregates are shown, together with Smad4 and Aβ, in the cancer stroma and peritumor capsules of many solid tumors. During lung cancer progression, for example, TIAF1 and amyloid fibrils are significantly upregulated in the cancer stroma. Aggregates of TIAF1 and Aβ are shown on the interface between metastatic lung cancer cells and the brain tissues. Conceivably, these peritumor materials are needed for cancer cells to survive. In vitro experiments revealed that TIAF1 is a crucial component for tumor suppressors p53 and WWOX-mediated tumor suppression and apoptosis. While metastatic lung cancer cells are frequently devoid of WWOX and p53, we provide new perspectives regarding the role of TIAF1 in the pathogenesis of lung cancer development, and propose a therapeutic approach for targeting TIAF1.

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Self-aggregating TIAF1 in lung cancer progression

Qunying Hong Li-Jin Hsu Pei-Yi Chou 0 Ying-Tsen Chou Chen-Yu Lu 0 Yu-An Chen 0 N n-Sh n Ch ng 0 1 0 Institute of Molecular Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan 1 Advanced Optoelectronic Technology Center, National Cheng Kung University , Tainan, Taiwan Recent studies have demonstrated that transforming growth factor beta (TGF-1)-induced antiapoptotic factor (TIAF1) is able to form aggregates in the hippocampi of middle-aged normal individuals. The aggregating TIAF1 induces generation of amyloid beta (A) for causing neurodegeneration. Intriguingly, TIAF1 aggregates are shown, together with Smad4 and A, in the cancer stroma and peritumor capsules of many solid tumors. During lung cancer progression, for example, TIAF1 and amyloid fibrils are significantly upregulated in the cancer stroma. Aggregates of TIAF1 and A are shown on the interface between metastatic lung cancer cells and the brain tissues. Conceivably, these peritumor materials are needed for cancer cells to survive. In vitro experiments revealed that TIAF1 is a crucial component for tumor suppressors p53 and WWOX-mediated tumor suppression and apoptosis. While metastatic lung cancer cells are frequently devoid of WWOX and p53, we provide new perspectives regarding the role of TIAF1 in the pathogenesis of lung cancer development, and propose a therapeutic approach for targeting TIAF1. - undergoes relocation to the nuclei in axotomized neurons in sciatic nerve transection in rats [6]. When WWOX undergoes activation via phosphorylation at Tyr33 (probably by SRC kinase), it binds a broad spectrum of proteins without the PPxY motif [3,5]. The domain structure of p53 includes a natively unfolded N-terminal transactivation domains TAD1 and TAD2, a proline-rich region (PRR), a central DNA-binding domain, and a C-terminal tetramerization domain [2,7]. Activated p53 causes cell cycle arrest, initiates DNA repair, and may lead to apoptosis [7]. p53 transactivates cyclin-dependent kinase inhibitor p21 or microRNA miR34 to induce cell cycle arrest [7]. For apoptosis, p53 transactivates proapoptotic genes such as BAX, PUMA, SCOTIN, and FAS, and inhibits the antiapoptotic gene BCL2 [7]. Under stress conditions (e.g. UV irradiation and chemotherapeutic drugs), activated WWOX physically binds Ser46phosphorylated p53. This binding allows WWOX to stabilize p53, and both proteins act together in causing apoptosis [3,5] (Figure 1). Role of p53 and WWOX in blocking cancer initiation and progression Cancer initiation and progression is generally considered as a consequence of gene mutation or epigenetic inactivation of tumor suppressors. It is believed that mutations in 2 Figure 1 WWOX signaling. The full-length WWOX or WOX1 has two N-terminal WW domains and a C-terminal short-chain alcohol dehydrogenase/reductase (ADH/SDR) domain [1-5]. A nuclear localization signal (NLS) is located between the WW domains. Sex steroid hormones may interact with the NSYK motif in the ADH/SDR domain [4,5]. Under stress stimuli, tyrosine kinase SRC and probably other kinases induce WWOX activation via Tyr33 phosphorylation. Activated WWOX binds Ser46-phosphorylated p53, and relocates to the mitochondria and nuclei to induce apoptosis. JNK1 and Zfra bind WWOX and counteract its-mediated apoptosis. The first WW domain of WWOX interacts with PPxY motif-containing transcription factors, including AP-2, p73, ERBB4, c-Jun and RUNX2. The binding allows transiently overexpressed WWOX to prevent relocation of transcription factors to the nucleus in vitro. However, the event does not work in vivo [6]. Phosphorylated Ezrin binds and anchors WWOX to the membrane/cytoskeleton area. Activated tyrosine kinase ACK1 phosphorylates WWOX at Tyr287 for polyubiquitination and proteosomal degradation. tumor suppressor genes cause cancer the so-called 2-hit hypothesis [8]. Recent development revealed that even partial inactivation of tumor suppressors critically contributes to tumorigenesis [8]. Despite these, it is not surprising to find that many tumor suppressor proteins, e.g. p53, WWOX, Smad4, and others, are significantly upregulated during the early stage of cancer progression [3,9,10]. Functional significance of these proteins in blocking cancer progression at the early stage is largely unknown. However, a good possibility is that these proteins are functionally inactivated. Proapoptotic p53, for example, is functionally inactivated by fortilin, an anti-apoptotic protein [11,12]. Fortilin physically interacts with the sequence-specific DNA binding domain of p53. Oncogenic monocarboxylic acid transporter 1 (MCT-1) abolishes the p53 function by enhancing its degradation via the ubiquitin/proteasome system [13]. Under stress conditions, NF-B acts as an oncoprotein to promote cell division and survival and block the proapoptotic function of p53 [14]. Mdm2 and Mdmx abolish the stability of p53 [15]. Mdm2 is an E3 ubiquitin ligase that causes p53 ubiquitination a (...truncated)


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Qunying Hong, Li-Jin Hsu, Pei-Yi Chou, Ying-Tsen Chou, Chen-Yu Lu, Yu-An Chen, Nan-Shan Chang. Self-aggregating TIAF1 in lung cancer progression, Translational Respiratory Medicine, 2013, pp. 5, Volume 1, Issue 1, DOI: 10.1186/2213-0802-1-5