Alteration of TEAD1 Expression Levels Confers Apoptotic Resistance through the Transcriptional Up-Regulation of Livin

Abstract

BackgroundTEA domain (TEAD) proteins are highly conserved transcription factors involved in embryonic development and differentiation of various tissues. More recently, emerging evidences for a contribution of these proteins towards apoptosis and cell proliferation regulation have also been proposed. These effects appear to be mediated by the interaction between TEAD and its co-activator Yes-Associated Protein (YAP), the downstream effector of the Hippo tumour suppressor pathway.Methodology/Principal FindingsWe further investigated the mechanisms underlying TEAD-mediated apoptosis regulation and showed that overexpression or RNAi-mediated silencing of the TEAD1 protein is sufficient to protect mammalian cell lines from induced apoptosis, suggesting a proapoptotic function for TEAD1 and a non physiological cytoprotective effect for overexpressed TEAD1. Moreover we show that the apoptotic resistance conferred by altered TEAD1 expression is mediated by the transcriptional up-regulation of Livin, a member of the Inhibitor of Apoptosis Protein (IAP) family. In addition, we show that overexpression of a repressive form of TEAD1 can induce Livin up-regulation, indicating that the effect of TEAD1 on Livin expression is indirect and favoring a model in which TEAD1 activates a repressor of Livin by interacting with a limiting cofactor that gets titrated upon TEAD1 up-regulation. Interestingly, we show that overexpression of a mutated form of TEAD1 (Y421H) implicated in Sveinsson's chorioretinal atrophy that strongly reduces its interaction with YAP as well as its activation, can induce Livin expression and protect cells from induced apoptosis, suggesting that YAP is not the cofactor involved in this process.Conclusions/SignificanceTaken together our data reveal a new, Livin-dependent, apoptotic role for TEAD1 in mammals and provide mechanistic insight downstream of TEAD1 deregulation in cancers.

A TEAD1/p65 complex regulates the eutherian-conserved MnSOD intronic enhancer, eRNA transcription and the innate immune response

“…We have also identified a novel serine residue (S180) in p65 that is required for MnSOD induction by cytokines and a S180T mutant supports this residue’s role as a potential phosphorylation site. Although the interaction and functional connection between TEAD1 and p65 has never been reported, they share a strikingly similar overlap in the control of physiological events including cellular senescence [55, 64], apoptotic resistance [65, 66], cell growth/differentiation [67, 68] and tumorigenesis [69, 70]. …”

Regulation of the Hippo Pathway Transcription Factor TEAD

“…Furthermore, the increase in metastatic potential in colorectal cancer was YAP independent as both wild-type TEAD4 and the YAP-binding deficient Y429 TEAD4 mutant rescued the effects of TEAD4 knockdown[71]. TEAD1 has been reported to play a role in conferring resistance to apoptosis in a YAP independent manner [72]. Additionally, TEAD1 was shown to regulate mesothelin, a gene that serves as a cancer biomarker due to its overexpression in many tumors [73].…”

Emerging roles of TEAD transcription factors and its coactivators in cancers

“…On the other hand, TEAD1 expression is downregulated in other breast cancer types and in renal or bladder cancers (www.oncomine.org). Interestingly, a recent study reconciles this seemingly opposing roles of TEADs in cancers by showing that both up and downregulation of TEAD causes increase in the expression of anti-apoptotic protein Livin 20 . Livin expression appears to favor cancer progression.…”

“…There is also up to a 300-fold increase in TEAD1 levels in Kaposi’s sarcoma (www.ebi.ac.uk/gxa). 20 Increased TEAD expression is also seen in basal-like breast cancers, 21 , 22 fallopian tube carcinoma 23 and germ cell tumors 24 . On the other hand, TEAD1 expression is downregulated in other breast cancer types and in renal or bladder cancers (www.oncomine.org).…”