Abstract
The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy.
Highlights
The Hippo signaling pathway is an evolutionarily-conserved signaling pathway that plays an important function in organ size control, tissue regeneration, as well as tumor suppression [1].YES-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the two main downstream effectors of the Hippo signaling pathway [2]
When cells are grown on a stiff matrix, YAP and TAZ become active and accumulate in the nucleus, which drive the expression of their target genes, such as connective tissue growth factor (CTGF) and ankyrin repeat domain 1 (ANKRD1)
Since siRNA knockdown of CTGF or cysteine-rich angiogenic inducer 61 (CYR61) has been shown to inhibit the growth of transformed mammary epithelial cells that express high levels of YAP or TAZ, it will be interesting to test whether these antibodies have an effect on YAP/TAZ-dependent tumors in humans
Summary
The Hippo signaling pathway is an evolutionarily-conserved signaling pathway that plays an important function in organ size control, tissue regeneration, as well as tumor suppression [1]. YES-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the two main downstream effectors of the Hippo signaling pathway [2]. YAP and TAZ function as transcriptional co-activators, and when they are active, they initiate a transcriptional program that enhances stem cell self-renewal and promotes cell proliferation, which are important for stimulating tissue regeneration. Aberrant and sustained activation of YAP and TAZ can lead to the formation of malignant tumors [3]. We present an overview of the Hippo signaling pathway, its role in tissue regeneration and tumorigenesis, as well as various approaches to modulate the Hippo signaling pathway for anticancer therapy and regenerative medicine
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