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Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression
G Franciosa1, G Diluvio1, F Del Gaudio1
1Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
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.
Insights
The prolyl-isomerase Pin1 targets Notch3, enhancing its activity and promoting T-cell Acute Lymphoblastic Leukemia (T-ALL) cell invasion. Inhibiting both Pin1 and Notch3 reduces T-ALL cell invasiveness and progression.
Area of Science:
- Molecular Biology
- Cancer Biology
- Immunology
Background:
- Deregulated Notch signaling is implicated in T-cell Acute Lymphoblastic Leukemia (T-ALL).
- The role of Notch pathway in leukemia cell invasion is recognized, but molecular mechanisms are unclear.
- Pin1 is a prolyl-isomerase involved in regulating protein function.
Purpose of the Study:
- To investigate the role of Pin1 in Notch3-mediated T-ALL progression.
- To identify Pin1 as a novel regulator of Notch3.
- To explore the therapeutic potential of targeting the Notch3-Pin1 axis in T-ALL.
Main Methods:
- Investigated the interaction between Pin1 and Notch3 in TALL-1 cells.
- Assessed the effect of combined Notch3 and Pin1 inhibition on cell invasiveness and MMP9 expression.
- Utilized a mouse model of Notch3-induced T-ALL to evaluate Pin1 depletion effects.
- Performed in silico gene expression analysis of human T-ALL samples.
Main Results:
- Pin1 directly targets Notch3, regulating its processing and stabilizing the intracellular domain (N3IC).
- Combined inhibition of Notch3 and Pin1 reduced invasiveness of TALL-1 cells by decreasing MMP9 expression.
- Pin1 depletion in a mouse model impaired T-ALL cell expansion and invasiveness.
- Significant correlation observed between Pin1 and Notch3 expression in human T-ALL samples.
Conclusions:
- The Notch3-Pin1 axis plays a critical role in T-ALL aggressiveness and progression.
- Combined suppression of Pin1 and Notch3 represents a potential therapeutic strategy for T-ALL.
- Targeting this axis may offer a novel approach to treat T-ALL by reducing tumor cell invasion.
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