P15RS and Wnt/β-Catenin Signaling
P15RS，a novel p15INK4b-related gene involved in G1/S progression，was identified by a differential display experiment from cells overexpressing P15INK4b，and regarded as a negative regulator in cell cycle control in G1 phase by down-regulating cyclin D1 expression. Wnt signaling is initiated by the binding of Wnt proteins to their receptors (Frizzled and LRP5/6) which branches into three distinct pathways, a Wnt-β-catenin pathway and two non-canonical pathways (Wnt-Ca2+ and Wnt-JNK). P15RS (a negative regulator of the cell cycle) blocks β-catenin-TCF4 complex formation and reduces Wnt signaling. Overexpression of P15RS reduces the interaction of β-catenin with TCF4, whereas the depletion of p15RS enhances their interaction. P15RS inhibits the Wnt signaling which initiates downstream gene expression by removing P15RS from promoters.
P15RS and Malignancy Inhibitory
P15RS is a ubiquitously expressed nuclear protein and regulated by P15, in turn, inhibits the expression of cyclin D and cyclin E. In a previous study, P15 was found to upregulate the expression of P15RS, which contains a CTD interacting domain (CID) that is present in the VHS/ENTH/ANTH superfamily of RNA processing proteins. In Xiaocui Zhang et al. study, while the P15RS expression had little effect on cell growth in monolayer cultures, it dramatically inhibited anchorage-independent cell growth in soft agar, a hallmark for malignancy. P15RS expression also inhibited cell migration and invasion which were key determinants of metastasis. Additionally, P15RS expression specifically downregulated the expression of cathepsin B and MMP-9 at RNA levels and promoted cell invasion through degrading extracellular matrix proteins. These results indicate that P15RS has malignancy-inhibitory functions independent of cell cycle inhibition and provides novel insight on the role of P15 in tumor inhibition.
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