Functional analysis of Cullin 3 E3 ligases in tumorigenesis

Abstract

Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.

Keywords: Cullin 3; Keap1; Mouse models; SPOP; Tumorigenesis; Ubiquitin.

Fig. 1.. Structural components of the Cullin-RING ligase family.

A. Cullin1-RING ligase complex; B. Cullin2-RING ligase complex; C. Cullin3-RING ligase complex; D. Cullin4A/4B-RING ligase complex; E. Cullin5-RING ligase complex; F. Cullin7-RING ligase complex; G. Cullin9-RING ligase complex; Ub: ubiquitin; NA: not available.

Fig. 2.

Functional illustrations of Keap1 and its specific substrates in tumorigenesis.

Fig. 3.

Functional illustrations of KLHL20 and its specific substrates in tumorigenesis.

Fig. 4.. Functional illustrations of SPOP and its specific substrates in tumorigenesis.

As indicated, SPOP plays tumor suppressor functions by targeting oncoproteins (ER, PR) in breast cancers and (SENP7, DAXX, ERG, SRC-3, DEK, TRIM24, AR, BRD2/3/4 and Gli2/3) in prostate cancer, while SPOP displays oncogenic functions by targeting tumor suppressor proteins (PTEN and DUSP7) in ccRCC.

Fig. 5.. Modular demonstrations of major Cul3 adaptors and therapeutically targeted sites.

A. Key functional modules inside human SPOP sequence and the targeted region of Compound 6b; B. Key functional modules inside human Keap1 sequence and the targeted region of CDDO-Me, DMF and MMF.