Oncogenic aberrations of cullin-dependent ubiquitin ligases

Abstract

Accumulating evidence points to a key role of the ubiquitin-proteasome pathway in oncogenesis. Aberrant proteolysis of substrates involved in cellular processes such as the cell division cycle, gene transcription, the DNA damage response and apoptosis has been reported to contribute significantly to neoplastic transformation. Cullin-dependent ubiquitin ligases (CDLs) form a class of structurally related multisubunit enzymes central to the ubiquitin-mediated proteolysis of many important biological substrates. In this review, we describe the role of CDLs in the ubiquitinylation of cancer-related substrates and discuss how altered ubiquitinylation by CDLs may contribute to tumor development.

The Emerging Role of the COP9 Signalosome in Cancer

“…Whether the CSN is a good therapeutic target remains controversial. Proponents argue that the pleiotropic functions that such inhibitors could affect in cancers are sufficient to pursue drug studies; opponents, however, suggest that inhibition could result in further genomic instability resulting in more aggressive cancers and might have large toxic effects on normal tissues (3,54). Knockdown of CSN5 in murine xenografts does significantly affect tumor growth, however, suggesting that this therapeutic paradigm may be worth pursuing (55).…”

“…Cullins are required for the degradation of key protooncogenes and tumor suppressors; therefore, a major goal for cancer biology will be to determine how this regulation becomes altered during tumorigenesis (3). There are seven Cullins expressed in humans that potentially couple to a large number of different E3 recognition components, although only a few of these complexes have been studied in any detail.…”

“…For instance, loss-of-function mutations of Cullin-1 in Caenorhabditis elegans result in a shortened G 1 phase and hyperplasia in all tissues (1)(2)(3). Cul1 is also required for correct cell cycle exit in the worm.…”

Ubiquitin Hubs in Oncogenic Networks

“…Additionally, Skp2 alone or in association with oncogenic Ras could induce tumor formation in two mouse models. On the other hand, Fbw7 has the features of a tumor suppressor, and indeed, inactivation mutations of the FBW7 gene have been detected in several ovarian and breast cancer cell lines expressing high levels of cyclin E. Furthermore, these mutations occur in primary endometrial carcinomas, where they may correlate with high tumor aggressiveness and scarce prognosis (6,13,15).…”

“…SCF/Skp2, which contains the Skp2 F-box protein, binds to and polyubiquitylates phosphorylated p27 and possibly cyclin D1, whereas SCF/Fbw7 targets phosphorylated cyclin E for proteasomal degradation. On the other hand, APC is required for the polyubiquitylation and degradation of securin and cyclin B, which are indispensable for sister chromatid separation and exit from mitosis, respectively (6,15).…”