On July 26th, research team from Beijing Institute of Biotechnology published a groundbreaking research paper titled "ABL1-mediated phosphorylation promotes FOXM1-related tumorigenicity by Increasing FOXM1 stability" in the journal "Cell Death & Differentiation" (impact factor: 13.7). 

The transcription factor FOXM1, known for its critical roles in cell cycle progression and tumorigenesis, is highly expressed in rapidly proliferating cells and various tumor tissues. Its high expression is associated with poor prognosis. However, the mechanisms underlying FOXM1 dysregulation remain poorly understood. A recent study by a research team has uncovered that the non-receptor tyrosine kinase ABL1 significantly contributes to the high expression of FOXM1 and FOXM1-dependent tumor development.

The study demonstrates that ABL1 directly binds to FOXM1 and mediates phosphorylation at multiple tyrosine (Y) residues. Among these phosphorylation sites, pY575 is essential for FOXM1 stability, as phosphorylation at this site protects FOXM1 from ubiquitin-proteasomal degradation. The interaction between FOXM1 and CDH1, a coactivator of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which is responsible for FOXM1 degradation, is significantly inhibited by Y575 phosphorylation. The phospho-deficient FOXM1(Y575F) mutant exhibited increased ubiquitination, a shortened half-life, and consequently a substantially decreased abundance.

Compared to wild-type cells, a homozygous Cr-Y575F cell line expressing endogenous FOXM1(Y575F) generated using CRISPR/Cas9 technology showed significantly delayed mitosis progression, impeded colony formation, and inhibited xenotransplanted tumor growth. These findings reveal the mechanism by which ABL1 kinase contributes to high FOXM1 expression, providing clear evidence that ABL1 may serve as a potential therapeutic target for treating tumors with high FOXM1 expression.

This study not only provides new insights into the molecular mechanisms of FOXM1 dysregulation but also opens new avenues for the treatment of tumors with high FOXM1 expression. This discovery lays the groundwork for developing anti-cancer drugs targeting ABL1 and holds significant potential for clinical applications. The researchers intend to further explore the role of ABL1 in tumors to validate its feasibility as a therapeutic target.

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