Fig. 3

Regulatory mechanisms of the stability, activation and expression of USP28. During the expression of USP28, both Tet1 and c-Jun can function on USP28 promoter and contribute to the enhancement of USP28 transcription. While miRNAs involving miR-363-3p which can be inhibited by USP28 substrate MYC, miR-500a-5p and miR-3940-5p have the capacity to interact with USP28 mRNA and then inhibit the translation of USP28. SUMOylation and LDHA can respectively suppresses and promotes the activation of USP28, and the former one can be antagonized by SENP1. Moreover, USP28 substrate HIF-1α can induce SENP1, thus forming a feedback loop. Besides, ubiquitination and caspase-8 can induce the destabilization of USP28, and HDAC5 brings about the inhibition of USP28 ubiquitination. ATG7 autophagy related protein 7, AUF1 ARE/poly(U)-binding/degradation factor 1, HDAC5 histone deacetylase 5, HIF-1α hypoxia-inducible factor-1α, LDHA lactate dehydrogenase A, SENP1 SUMO-specific protease 1, SUMO small ubiquitin-like modifier, Tet1 Ten-eleven translocation 1, Ub ubiquitin, USP28 ubiquitin-specific protease 28