Abstract
Hippo pathway is a highly conservative signalling pathway related to the development of organisms, which has been demonstrated to be strongly linked to the tumorigenesis and tumour progression. As the major downstream effector of Hippo pathway, yes-associated protein (YAP), is a transcriptional activator of target genes that are involved in cell proliferation and survival. As an oncogene, YAP can promote cell growth and inhibit cell apoptosis. Another major downstream effector of Hippo pathway, transcriptional co-activators with PDZ-binding motif (TAZ), is nearly 60% homologous with YAP. In the present study, we assume that TAZ probably has the similar function to YAP. To test this issue, we established an inducible and a stable expression system of TAZ in T-Rex-293 and HEK293 cells respectively. The results of cell growth curves, colony formation assay and tumour xenograft growth showed that overexpression of TAZ could promote cell growth invitro and invivo Meanwhile, we found that up-regulated expression of TAZ could partially restore Celastrol-induced cell apoptosis. Induced overexpression of TAZ could up-regulate its target genes including ankyrin repeat domain-containing protein (ANKRD), cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF), increase the expression of B-cell lymphoma-2 (Bcl-2), decrease the expression of Bcl-2 associated X protein (Bax) and activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which may be the mechanism underlying anti-apoptosis of TAZ. All these findings indicated that TAZ acts as an oncogene that could be a key regulator of cell proliferation and apoptosis.
Highlights
Hippo pathway, first discovered in Drosophila, aims at adjusting the organ size, maintaining the dynamic balance of cell proliferation, apoptosis and other functions [1]
Our study proved that transcriptional co-activators with PDZ-binding motif (TAZ) could act as an oncogene to promote cell proliferation and inhibit cell apoptosis
The cell growth curves showed that 293-TR/TAZ cells grew obviously faster when treated with Dox, and the growth rate of the other three groups (293-TR/TAZ cells without Dox and 293-TR/control cells with Dox or not) were nearly the same (Figure 1B)
Summary
First discovered in Drosophila, aims at adjusting the organ size, maintaining the dynamic balance of cell proliferation, apoptosis and other functions [1]. With the abnormal Hippo pathway, the cells will proliferate excessively or apoptosis insufficiently, and the organ will grow out of control, which will eventually lead to the tumorigenesis and tumour progression [2]. The cores of Hippo pathway consist of the mammalian sterile20like kinases serine/threonine kinases 1/2 (MST1/2), the large tumour suppressor serine/threonine protein kinases 1/2 (LATS1/2), as well as their scaffold proteins Salvador homologue 1 (SAV1; called WW45) and Mps one binder kinase activator proteins (MOBs). Activated LATS1/2 phosphorylate the transcriptional regulators, including yes-associated protein (YAP) and transcriptional co-activators with PDZ-binding motif (TAZ). As the transcriptional regulators, YAP/TAZ bind to multiple transcription factors, such as TEADs, Smads, PAXs, TBX5 and RUNX2 [6], and regulate genes involved in stemness, differentiation, proliferation and apoptosis via nuclear translocation
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