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.
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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)