YB-1 is a Transcription/Translation Factor that Orchestrates the Oncogenome by Hardwiring Signal Transduction to Gene Expression

Abstract

The Y-box Binding Protein-1 (YB-1) is a highly conserved oncogenic transcription/translation factor that is expressed in cancers affecting adults and children. It is now believed that YB-1 plays a causal role in the development of cancer given recent work showing that its expression drives the tumorigenesis in the mammary gland. In human breast cancers, YB-1 is associated with rapidly proliferating tumors that are highly aggressive. Moreover, expression of YB-1 promotes the growth of breast cancer cell lines both in monolayer and anchorage independent conditions. The involvement of YB-1 in breast cancer pathogenesis has made it a putative therapeutic target; however, the mechanism(s) that regulate YB-1 are poorly understood. This review first describes the oncogenic properties of YB-1 in cancer. It also highlights the importance of YB-1 in hardwiring signal transduction pathways to the regulation of genes involved in the development of cancer.

Keywords: YB-1; cancer; phosphorylation; signal transduction.

Figure 1

The Structure and Functions of YB-1. YB-1 is made up of the N-terminal, cold shock (CSD) and C-terminal domains (CTD). These domains have unique functions. The N-terminal is necessary for transactivation whereas the CSD is important for RNA/DNA binding. Most of the characterized protein:protein interactions occur on the CTD. The CSD and CTD also work together to facilitate nuclear trafficking. Cellular trafficking is furthermore regulated by the nuclear localization signal in the C-terminal domain as well as the cytoplasmic retention signal also located in this region of the protein.

Figure 2

Putative YB-1 regulatory sites were predicted using CONSITE. (A) The YB-1 promoter (−2kB) was evaluated for potential regulatory elements using CONSITE against all conserved species where the stringency was set at 90%. (B) Alternatively, if only the human database was used, at a 90% cut-off, additional regulatory elements were identified. Finally, evaluating the human database with 100% stringency revealed that N-Myc and Snail binding sites were present.

Figure 3

Summary of where signaling pathways potentially phosphorylate YB-1 and how these post-translational changes could impact its function. In this review, we have highlighted the fact that YB-1 is phosphorylated by Akt at S102 which occurs in the CSD. The consequence of S102 phosphorylation is a change in DNA binding. It also impact YB-1’s ability to regulate translation. Because PKC and RSK also have the potential to phosphorylate S102 it is conceivable that they too could alter YB-1’s transcriptional and translational capacities. GSK and ERK1 have the potential to phosphorylate YB-1 at S21 and S36 respectively, which could alter YB-1’s ability to transactivate. Alternatively the p85 subunit of PI3K could regulate YB-1 by phosphorylating Y197, which resides within the nuclear localization sequence. It is therefore possible that Pi3K could phosphorylate YB-1 and thereby stimulate nuclear trafficking.

Figure 4

Schematic of the multiple functions of YB-1 in cancer cells. Signal transduction is initiated by growth factor such as IGF-1 and cytokines leading to the activation of kinases that could potentially phosphorylate YB-1. It is generally thought that YB-1 is phosphorylated by kinases such as AKT in the cytoplasm leading to nuclear trafficking and DNA binding. The phosphorylation of YB-1 can also alter its role in translation initiation, mRNA splicing and/or transport. In the nucleus, YB-1 binds to multiple genes involved in tumor cell growth by directly binding to inverted CAAT boxes. It also indirectly induces the expression of oncogenes by coupling to other transcription factors such as AP-1 and p53. YB-1 can thus induce the expression of oncogenes through transcriptional as well as translational control.