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Musashi Signalling

Model exemplifying downstream mediators of Musashi’s impact in development and cancer. (a) In normal stem cells, Musashi expression suppresses Numb translation, leading to increased Notch signaling and maintenance of an undifferentiated state. Musashi can also suppress p21 (also known as Cdnk1a), which normally blocks cell cycle progression, thus promoting cell proliferation. (b) As Musashi expression is extinguished, suppression of Numb is lost and Notch signaling is inhibited, thus triggering differentiation. In parallel, reduced Musashi expression results in increased levels of p21 and reduced cell proliferation. (c) In the context of cancer, increased levels of Musashi suppress Numb and p21, among other genes, leading to sustained self-renewal of the cancer stem cell pool.

Musashi in Cancer

Potential mechanisms of action for the Musashi family of proteins. (a) Repression of translation. When Musashi binds to consensus sequences in the 3’ untranslated region (UTR) of a target messenger RNA (mRNA) (star), it can also interact with poly-A binding protein (PABP) via a separate domain in its C-terminal half. This interaction competes with eIF4G (not shown) for PABP, resulting in blockade of ribosome assembly and translation. (b) Activation of translation. When Musashi is bound to the poly(A) polymerase GLD2, GLD2-mediated polyadenylation stabilizes mRNA targets, resulting in increased translation. (c) Enhancement of LIN28 function. Musashi1 associates with LIN28 in an RNA-dependent fashion in the cytoplasm. Some evidence suggests that Musashi1 can influence nuclear import of LIN28, potentially via interaction with Importin-α. In the nucleus (purple circle), Musashi1 binds to LIN28 in an RNA-independent manner and may enhance the inhibition of microRNA processing.

Mechanism of Action

Potential mechanisms of action for the Musashi family of proteins. (a) Repression of translation. When Musashi binds to consensus sequences in the 3’ untranslated region (UTR) of a target messenger RNA (mRNA) (star), it can also interact with poly-A binding protein (PABP) via a separate domain in its C-terminal half. This interaction competes with eIF4G (not shown) for PABP, resulting in blockade of ribosome assembly and translation. (b) Activation of translation. When Musashi is bound to the poly(A) polymerase GLD2, GLD2-mediated polyadenylation stabilizes mRNA targets, resulting in increased translation. (c) Enhancement of LIN28 function. Musashi1 associates with LIN28 in an RNA-dependent fashion in the cytoplasm. Some evidence suggests that Musashi1 can influence nuclear import of LIN28, potentially via interaction with Importin-α. In the nucleus (purple circle), Musashi1 binds to LIN28 in an RNA-independent manner and may enhance the inhibition of microRNA processing.