TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death

Abstract

Self-aggregation of transforming growth factor β (TGF-β)1-induced antiapoptotic factor (TIAF1) is known in the nondemented human hippocampus, and the aggregating process may lead to generation of amyloid β (Aβ) for causing neurodegeneration. Here, we determined that overexpressed TIAF1 exhibits as aggregates together with Smad4 and Aβ in the cancer stroma and peritumor capsules of solid tumors. Also, TIAF1/Aβ aggregates are shown on the interface between brain neural cells and the metastatic cancer cell mass. TIAF1 is upregulated in developing tumors, but may disappear in established metastatic cancer cells. Growing neuroblastoma cells on the extracellular matrices from other cancer cell types induced production of aggregated TIAF1 and Aβ. In vitro induction of TIAF1 self-association upregulated the expression of tumor suppressors Smad4 and WW domain-containing oxidoreductase (WOX1 or WWOX), and WOX1 in turn increased the TIAF1 expression. TIAF1/Smad4 interaction further enhanced Aβ formation. TIAF1 is known to suppress SMAD-regulated promoter activation. Intriguingly, without p53, self-aggregating TIAF1 spontaneously activated the SMAD-regulated promoter. TIAF1 was essential for p53-, WOX1- and dominant-negative JNK1-induced cell death. TIAF1, p53 and WOX1 acted synergistically in suppressing anchorage-independent growth, blocking cell migration and causing apoptosis. Together, TIAF1 shows an aggregation-dependent control of tumor progression and metastasis, and regulation of cell death.

Role of WW Domain-containing Oxidoreductase WWOX in Driving T Cell Acute Lymphoblastic Leukemia Maturation

“…We utilized yeast two-hybrid analysis (21-23) and FRET (26,28,42,43) to map the domain/domain interactions between WWOX and IB␣. By Cytotrap yeast two-hybrid assay, we determined that IB␣-(1-67) (amino acid #1-67) and the ankyrin domain of IB␣-(68 -243) (amino acid #68 -243) bound the full-length WWOX (Fig.…”

“…IB␣ may undergo degradation upon release from mitochondria. We have recently reported the shuttling of TRAPPC6A (trafficking protein particle complex 6A) in between nucleolus and mitochondrion (42,43). TRAPPC6A is a carrier for WWOX to undergo nuclear translocation.…”

“…WWOX is anchored on the membrane by binding with Hyal-2 (26), Ezrin (47,48), and other membrane proteins. WWOX is involved in the TGF-␤ signaling (26,42,43,49). Whether IoP cross-talks with TGF-␤ signaling and activates membrane Hyal-2/WWOX remains to be established.…”

Introduction to a Thematic Issue for WWOX

“…15 WWOX physically interacts with proteins associated with Alzheimer's diseases (AD). 13 Proteins of this category include TRAPPC6A, 16 TIAF1, 17,18 Tau, 7 GSK-3b, 19 JNK1, 7,20 ERK, 7,21 and many other unidentified proteins. WWOX is frequently down-regulated in the hippocampi of AD brains.…”

Molecular dynamics of the full-length p53 monomer

“…A recently discovered, relevant set of novel p53 targets include the metabolism of the cell, 17,18 for example the pathways of mevalonate, 19,20 serine, 21 malate, 22 and glutaminolysis. 23 This results in the regulation of cell death 24 or cell cycle. [25][26][27] A relevant metabolic role of p53 is exerted during hypoxia, as oxygen relative pressure reaches particularly lower levels at the center of the tumors, where p53 protein interplays with mTOR 28 as well as with the more classic pathways of HIF-1a and VHL.…”