Abstract
Deregulated Notch signaling is associated with T-cell Acute Lymphoblastic Leukemia (T-ALL) development and progression. Increasing evidence reveals that Notch pathway has an important role in the invasion ability of tumor cells, including leukemia, although the underlying molecular mechanisms remain mostly unclear. Here, we show that Notch3 is a novel target protein of the prolyl-isomerase Pin1, which is able to regulate Notch3 protein processing and to stabilize the cleaved product, leading to the increased expression of the intracellular domain (N3IC), finally enhancing Notch3-dependent invasiveness properties. We demonstrate that the combined inhibition of Notch3 and Pin1 in the Notch3-overexpressing human leukemic TALL-1 cells reduces their high invasive potential, by decreasing the expression of the matrix metalloprotease MMP9. Consistently, Pin1 depletion in a mouse model of Notch3-induced T-ALL, by reducing N3IC expression and signaling, impairs the expansion/invasiveness of CD4+CD8+ DP cells in peripheral lymphoid and non-lymphoid organs. Notably, in in silico gene expression analysis of human T-ALL samples we observed a significant correlation between Pin1 and Notch3 expression levels, which may further suggest a key role of the newly identified Notch3-Pin1 axis in T-ALL aggressiveness and progression. Thus, combined suppression of Pin1 and Notch3 proteins may be exploited as an additional target therapy for T-ALL.
Highlights
Notch pathway is an evolutionarily conserved signaling pathway, which has an important role in cell-fate determination and differentiation in many tissues.[1]
We evaluated the possible crosstalk between Pin[1] and Notch proteins in T-cell Acute Lymphoblastic Leukemia (T-ALL) context, by analyzing human T-ALL cell lines and a mouse model of Notch3-induced T-ALL.[7]
The levels of Notch3 intracellular region (N3IC) decreased in all the cell lines analyzed, independently of Notch[1] activation status, as revealed by the immunoreactivity to the anti-Notch1Val1744 antibody (Figure 1c)
Summary
Notch pathway is an evolutionarily conserved signaling pathway, which has an important role in cell-fate determination and differentiation in many tissues.[1]. T-ALL implies that other mechanisms such as transcriptional, epigenetic, post-translational or a combination of these are responsible for its overexpression. Altered degradation process and/or acetylation/deacetylation balance have been shown to have an important role in the control of Notch[3] protein stability,[12,13] contributing to the sustained Notch[3] overexpression and Notch3dependent leukemia development in Notch[3] transgenic mice.[7] These observations suggest that Notch[3] expression can be modified by more than one type of post-translational modification (PTM) event.[14]
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