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  • Heat shock proteins as molecular chaperones are involved


    Heat shock proteins, as molecular chaperones, are involved in a variety of cellular functions. Apart from their commonly known roles in maintaining protein stability and mediating the assembly and disassembly of protein complexes, recent studies have shown that certain chaperones, including HSPA8, also regulate the dynamic formation of protein-DNA complexes involved in biological processes such as transcription, telomere maintenance, DNA repair, and DNA replication (Ahn et al., 2005; DeZwaan and Freeman, 2010). Although a previous report has demonstrated a regulatory role of the chaperone protein Hsp90 in maintaining mESC pluripotency through interacting with the core pluripotency factors (Bradley et al., 2012), the possible role of chaperones in directly regulating the DNA-binding and, subsequently, the transcription-activation activities of the core pluripotency factors has yet to be investigated. Our study examined this potential molecular mechanism and unveiled a function of the chaperone protein HSPA8 in maintaining hESC pluripotency by directly facilitating the transcription-activation activity of the master pluripotency factor OCT4. Our study also adds another HSPA8/HSP70 inhibitor, Displurigen, to the current reservoir of bioactive small molecules. The modulation of heat shock protein activities has been studied extensively for potential clinical applications such as cancer therapy. In contrast to normal cells, cancer ARQ 621 cost strongly overexpress HSP70 to provide resistance to stresses generated by the environment, from tumorigenesis events, and during cancer therapy. This addiction to HSP70 provides the theoretical basis for its targeting in anti-cancer treatment (Goloudina et al., 2012; Jego et al., 2013). In recent years, several HSPA8/HSP70 inhibitors have been discovered and studied for their applications in anti-cancer therapies (Goloudina et al., 2012). The discovery of Displurigen expands this growing list of HSPA8/HSP70 inhibitors and provides a drug candidate for cancer therapy.
    Experimental Procedures
    Author Contributions
    Introduction Pluripotent stem cells (PSCs) are characterized by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. Great knowledge exists about the regulatory networks that maintain pluripotency and about key players that regulate differentiation. Pluripotency exists in various states, with the ground state of naive pluripotency as the most basic state of pluripotency (Chen et al., 2013; Leitch et al., 2013; Wray et al., 2010). Here, diverse signaling pathways, in concert with a combination of key transcription factors (TFs), precisely regulate ground state conditions. Diminutive changes in their expression can either destabilize or strengthen the network (Karwacki-Neisius et al., 2013). Several network TFs are heterogeneously expressed (Chambers et al., 2007; Festuccia et al., 2012; Kalmar et al., 2009; MacArthur et al., 2012; Miyanari and Torres-Padilla, 2012; Papatsenko et al., 2015) and regulated in a highly dynamic manner to balance between stem cell self-renewal and exit from pluripotency (Faddah et al., 2013; Radzisheuskaya et al., 2013) as well as during somatic reprogramming (Takahashi and Yamanaka, 2006). Finally, even core TFs of the pluripotency network determine the exit from stemness to early cell fate determination in a competitive manner (Lu et al., 2011; Teo et al., 2011; Waghray et al., 2015; Weidgang et al., 2013). The T-box family of TFs is involved in a variety of signaling cascades including the pluripotency network (Niwa et al., 2009). TBX3 mutually regulates the expression of key lineage TFs factors while maintaining and inducing pluripotency (Han et al., 2010a; Weidgang et al., 2013). In detail, TBX3 is directly bound by NANOG and in turn binds OCT4 and SOX2 (Han et al., 2010a). Its expression is regulated in part by the phosphatidylinositol-3-OH-kinase-Akt (PI3K) and mitogen-activated protein kinase (MAPK) pathways (Niwa et al., 2009). Moreover, TBX3 can bypass the requirement for leukemia inhibitory factor (LIF) signaling and functions upstream of NANOG in PSCs (Niwa et al., 2009). Removal of TBX3 from embryonic stem cells (ESCs) causes differentiation (Han et al., 2010a; Ivanova et al., 2006; Lee et al., 2012; Lu et al., 2011; Nishiyama et al., 2013). In contrast, TBX3 is also a crucial player in early cell fate events, driving mesendodermal and primitive endoderm (PE) specification (Kartikasari et al., 2013; Lu et al., 2011; Waghray et al., 2015; Weidgang et al., 2013). Here, we provide a comprehensive view on the definitive requirements for TBX3 to maintain and induce pluripotency and precisely characterize various TBX3-expression states in PSCs.