Fig. 4: Schematic illustration of mechanisms leading to oncogenic NRF2 activation. | Oncogenesis

Fig. 4: Schematic illustration of mechanisms leading to oncogenic NRF2 activation.

From: A novel uterine leiomyoma subtype exhibits NRF2 activation and mutations in genes associated with neddylation of the Cullin 3-RING E3 ligase

Fig. 4

NRF2 is, under basal conditions, ubiquitinated by the KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex. Neddylation is required for the activation of cullin-RING ubiquitin ligases (CRL). The COP9 signalosome (CSN) is responsible for deneddylation of CRL. KEAP1 plays a central role in regulating the activity of NRF2. In cancers, the interaction between the E3 subunits can be disrupted by specific mutations in NFE2L2 (encoding NRF2) or by biallelic loss of KEAP1 or CUL3 (yellow stars). The interaction between NRF2 and KEAP1 can also be disrupted by protein succination of critical cysteine residues within KEAP1 as a result of fumarate accumulation. Oncogenic activation of the NRF2 pathway can be seen in uterine leiomyomas that harbor biallelic loss of FH or biallelic loss of key members involved in the neddylation pathway (red stars). Finally, inhibition of neddylation by MLN4924 or DI-591 results in activation of NRF2.

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