MAPK and PI3K/AKT mediated YB‐1 activation promotes melanoma cell proliferation which is counteracted by an autoregulatory loop

Abstract

Y-box binding protein 1 (YB-1) is an oncogenic transcription and translation factor and is overexpressed in several types of cancer. Our previous data showed that YB-1 is upregulated and translocated to the nucleus during melanoma progression and that YB-1 is an important transcription factor regulating proliferation, survival, migration, invasion and chemosensitivity of melanoma cells. It has been suggested that YB-1 is activated and translocated to the nucleus after S102-phosphorylation in the DNA binding domain. In this study, we show that activation of YB-1 by S102-phosphorylation and nuclear translocation is increased during melanoma progression using a human tissue microarray with 100 melanocytic lesions. Furthermore, we analysed the mechanisms governing the expression and activity of YB-1 in melanoma cells. We show that the PI3K/AKT and p53 signalling, growth factors and chemotherapeutic agents increase YB-1 promoter activity. This, however, resulted in no or only modest increase in YB-1 protein expression. We show that the MAPK and PI3K/AKT signalling pathways, both activated in melanoma cells, as well as p53 overexpression increase YB-1 S102-phosphorylation, whereas NFκB signalling inhibits phosphorylation. Overexpression of YB-1 in melanoma cells inhibits translation efficiency and by this proliferation and survival of melanoma cells indicating that there is an autoregulatory loop restricting YB-1 protein expression. These data suggest that there is a tightly regulated feedback mechanism regulating YB-1 expression and activation, necessary for proper cell cycle progression of melanoma cells.

Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells

“…93−95 The inhibition of the PI3K pathway can also reduce the expression of YBX1. 95 Additionally, a reduction in YBX1 leads to a marked decrease in mTOR protein levels. 96 Interestingly, TCTP is also involved in PI3K/Akt/mTOR signaling.…”

Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy

“…These include PIASy [56], Tip60 [56,57], Y box-binding protein 1 [58,59], p63 [60], and p73 [61]. Both p63 and p73 are rarely mutated in human cancer.…”

Nuclear shuttling of Y Box binding protein-1, its clinical relevance in cancer and as a therapeutic target

“…Up-regulated YB-1 in breast cancer facilitates monolayer and anchorage independent growth. Thus, it shows a relationship between YB-1 and EGFR in BLBC (Mertens et al, 1998) as EGFR signals through MAPK pathway (Sinnberg et al, 2012) and p90 ribosomal S6 kinase also phosphorylates YB-1 (Stratford et al, 2008). Till date many growth promoting genes form YB-1 target (Jensen et al, 1999).…”

“…At the end, long C-terminal domain (130-324) contains positive and negative charged clusters. Each cluster is nearly 25-30 amino acids long and present alternatively (Kloks et al, 2002) signaling such as P13K/AKT, RSK, Ras/MAPK (Dalby et al, 1998;Lorsch, 2002;Sinnberg et al, 2012;Shen et al, 2011;Astanehe et al, 2012) and PKC signaling (Fujii et al, 2009) cascades. Another mechanism involves the proteasome-mediated cleavage of YB-1 between NLS and cytoplasmic retention sequence which further triggers the gathering of trimmed YB-1 deficient in cytoplasmic retention sequence in DNA damaged cell nuclei in vitro as well as in vivo in response to genotoxic stress .…”

“…Till date many growth promoting genes form YB-1 target (Jensen et al, 1999). The phosphorylation of YB-1 at S102 site is carried out by PI3K pathway as well as MAPK pathway (Sinnberg et al, 2012). As compared to AKT1 dependent phosphorylation, RSK1 and RSK2 are more specific in phosphorylating YB-1 at S102 (Startford et al., 2008).…”