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Fig. 2 | Journal of Biomedical Science

Fig. 2

From: Ubiquitination by HUWE1 in tumorigenesis and beyond

Fig. 2

HUWE1-mediated proliferation/differentiation. a HUWE1 is regulated by WNT and ubiquitinates Dvl via K63-linkage, which subsequently inhibits multimerization of Dvls, contributing to the negative feedback loop in the Wnt/β-catenin pathway. b HUWE1 is able to enhance tumor proliferation by K63-ubiquitinating c-Myc, which facilitates the recruitment of CBP/p300, therefore enhancing the transactivation activity of c-Myc. HUWE1 sustains normal ovarian epithelial cell transformation and tumor growth by ubiquitinating histone H1.3. Ubiquitinated H1.3 is subsequently degraded, releasing H1.3 from the imprinting control region (ICR) of the distal promoter region of an oncogenic non-coding RNA, H19. HUWE1 also mediates K48-linked polyubiquitination of N-myc and facilitates its degradation. Loss of N-myc can arrest proliferation via cell cycle and begin differentiation in neural stem/progenitor cells. Loss of N-myc by HUWE1 can also disrupt the neural stem cell activity through the DLL3-Notch pathway in the mouse cortex. In hematopoietic stem cells (HSCs), loss of HUWE1 increases N-myc-dependent proliferation and thus HUWE1 is a key regulator in the maintenance and lymphoid commitment of HSCs. c HUWE1 regulates SHH-type medulloblastoma (MB) via ubiquitinating and controlling Atoh1 protein turnover. Atoh1, a crucial basic helix-loop-helix transcription factor for granule neuron progenitors (GNPs), inhibits neuronal differentiation and enhances MB formation

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