Abstract
The Hippo pathway regulates cell proliferation and apoptosis through the Yes-associated protein (YAP) transcriptional activator. YAP has a well-described role in promoting cell proliferation and survival, but the precise mechanisms and transcriptional targets that underlie these properties are still unclear and likely context-dependent. We found, using siRNA-mediated knockdown, that YAP is required for proliferation in endothelial cells but not HeLa cells. Specifically, YAP is required for S-phase entry and its absence causes cells to accumulate in G1. Microarray analysis suggests that YAP mediates this effect by regulating the transcription of genes involved in the assembly and/or firing of replication origins and homologous recombination of DNA. These findings thus provide insight into the molecular mechanisms by which YAP regulates cell cycle progression.
Highlights
The evolutionarily conserved Hippo pathway regulates cell proliferation, apoptosis, migration and cell fate specification through the Yes-associated protein (YAP) transcriptional regulator [1,2,3,4,5]
YAP is required for human umbilical vein endothelial cells (HUVECs) proliferation and cell cycle progression
It is important to note that YAP knockdown (YAP-KD) cells exhibited a significantly lower percentage of both arrested S (Fig. 3B) and normal S (Fig. 3C-E) which was likely the effect of YAP siRNA, not a result of APH treatment. These results demonstrate that YAP is not required for S-phase progression, as both control and YAP-KD HUVECs were capable of resuming the S phase after APH removal
Summary
The evolutionarily conserved Hippo pathway regulates cell proliferation, apoptosis, migration and cell fate specification through the YAP transcriptional regulator [1,2,3,4,5]. High levels of Yap, achieved through mis-expression of YAP itself or deletion of upstream negative regulators, results in increased cell proliferation and carcinogenesis in many tissues [6,7,8,9,10,11,12,13,14,15]. Elevated levels of YAP have been detected in multiple human cancers, where it has been associated with poor prognosis in some cases [14,16,17,18]. Microarray analysis of mouse Yap transgenic livers detected increased expression of multiple cell cycle regulators such as c-Myc, cyclin D, cyclin B, cyclin E and CDK6. Yap transgene induction stimulated the expression of survival genes including
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