Abstract
NUMB, and its close homologue NUMBL, behave as tumor suppressor genes by regulating the Notch pathway. The downregulation of these genes in tumors is common, allowing aberrant Notch pathway activation and tumor progression. However, some known differences between NUMB and NUMBL have raised unanswered questions regarding the redundancy and/or combined regulation of the Notch pathway by these genes during the tumorigenic process. We have found that NUMB and NUMBL exhibit mutual exclusivity in human tumors, suggesting that the associated tumor suppressor role is regulated by only one of the two proteins in a specific cell, avoiding duplicate signaling and simplifying the regulatory network. We have also found differences in gene expression due to NUMB or NUMBL downregulation. These differences in gene regulation extend to pathways, such as WNT or Hedgehog. In addition to these differences, the downregulation of either gene triggers a cancer stem cell-like related phenotype. These results show the importance of both genes as an intersection with different effects over cancer stem cell signaling pathways.
Highlights
NUMB and NUMBL, or NUMB-Like, belongs to a closely conserved family of proteins with important roles in a large variety of cellular processes ranging from cell adhesion to ubiquitination [1,2,3,4,5,6,7]
We found that the negative correlation of NUMB/NUMBL was present in non-tumoral samples, showing that both genes are to some extent mutually exclusive in cells (Supplementary Figure 1)
Their expression in non-tumoral samples, which is close to 75%, shows that this opposite regulation is a common effect in human cells. Their role as negative regulators of the Notch pathway likely requires a higher transcription of one of the genes than the other, allowing only one of the two proteins to effectively perform its regulatory role. This notion is supported by development studies conducted in mouse and chicken embryos, where NUMB is broadly expressed, while NUMBL appears to be enriched in the developing central nervous system [9,10,11]
Summary
NUMB and NUMBL, or NUMB-Like, belongs to a closely conserved family of proteins with important roles in a large variety of cellular processes ranging from cell adhesion to ubiquitination [1,2,3,4,5,6,7]. Knock-out experiments in mice have shown that, NUMBL deletion showed no differences during embryogenesis, the deletion of NUMB or combined NUMB/NUMBL deletion were embryonic lethal [6, 12, 13]. Together, these differences show that, NUMB and NUMBL have a conserved structure and domains [14], the functional differences between the proteins must be considered
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