The RNA-binding protein Musashi-1 regulates proteasome subunit expression in breast cancer- and glioma-initiating cells.

Abstract

Cancer stem cells (CSCs) or tumor-initiating cells, similar to normal tissue stem cells, rely on developmental pathways, such as the Notch pathway, to maintain their stem cell state. One of the regulators of the Notch pathway is Musashi-1, a mRNA-binding protein. Musashi-1 promotes Notch signaling by binding to the mRNA of Numb, the negative regulator of Notch signaling, thus preventing its translation. CSCs have also been shown to downregulate their 26S proteasome activity in several types of solid tumors, thus making them resistant to proteasome-inhibitors used as anticancer agents in the clinic. Interestingly, the Notch pathway can be inhibited by proteasomal degradation of the Notch intracellular domain (Notch-ICD); therefore, downregulation of the 26S proteasome activity can lead to stabilization of Notch-ICD. Here, we present evidence that the downregulation of the 26S proteasome in CSCs constitutes another level of control by which Musashi-1 promotes signaling through the Notch pathway and maintenance of the stem cell phenotype of this subpopulation of cancer cells. We demonstrate that Musashi-1 mediates the downregulation of the 26S proteasome by binding to the mRNA of NF-YA, the transcriptional factor regulating 26S proteasome subunit expression, thus providing an additional route by which the degradation of Notch-ICD is prevented, and Notch signaling is sustained.

• Authors: Chann Lagadec, Erina Vlashi, Patricia Frohnen, Yazeed Alhiyari, Mabel Chan, Frank Pajonk
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 32 Issue 1 Pg. 135-44 (Jan 2014) ISSN: 1549-4918 [Electronic] England
• PMID: 24022895 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © AlphaMed Press.

Chemical References

• CCAAT-Binding Factor
• MSI1 protein, human
• Nerve Tissue Proteins
• RNA, Messenger
• RNA, Small Interfering
• RNA-Binding Proteins
• nuclear factor Y
• Proteasome Endopeptidase Complex
• ATP dependent 26S protease

Topics

• Breast Neoplasms (enzymology, genetics, metabolism, pathology)
• CCAAT-Binding Factor (genetics, metabolism)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Down-Regulation
• Female
• Glioma (enzymology, genetics, metabolism, pathology)
• Humans
• Neoplastic Stem Cells (enzymology, metabolism, pathology)
• Nerve Tissue Proteins (genetics, metabolism)
• Proteasome Endopeptidase Complex (biosynthesis, genetics)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (administration & dosage, genetics)
• RNA-Binding Proteins (genetics, metabolism)
• Signal Transduction
• Transfection