Similar, not the same: Diverse roles and regulation of cyclin Es

Cell cycle deregulation and genomic instability play a major role in the aberrant cell proliferation that characterizes tumorigenesis. A novel role of the cyclin E isoform cyclin E2 in these processes is reported in the manuscript “Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1” by Caldon et al.1 In another issue of “Cell Cycle,” evidence that regulation of cyclin E2 stability is uncoupled from cyclin E1 regulation in cancer cells is described in the manuscript “Differences in degradation lead to asynchronous expression of cyclin E1 and cyclin E2 in cancer cells” by the same research group.2

The major role of cyclin E is promotion of G1– to S-phase transition through Cdk2 activation. Involvement in other activities such as pre-replication complexes formation3 and centrosome duplication has also been identified for cyclin E1.4 The cyclin E/Cdk2 complex is in part regulated by the increased expression of cyclin E in late G1 phase5 and its destruction by ubiquitin-mediated proteasomal degradation in S phase (reviewed in ref. 6). Due to their high sequence similarity, cyclin E1 and E2 have been regarded as functionally redundant, and where the isoforms are even considered, cyclin E1 is generally studied as the prototypic cyclin E. However, knockout mouse models have revealed tissue-specific functions in male fertility7 and liver regeneration.8 In cancer, there is also evidence for cyclin E isoform-specific functions (reviewed in ref. 9). Cyclin E1 and cyclin E2 are independent prognostic indicators in different breast cancer cohorts, and unlinked co-expression of cyclin E1 and E2 has been observed in several other types of cancers, with cyclin E2 commonly associated with the relapsing forms of the disease. However, while there is strong evidence for cyclin E1 overexpression promoting tumorigenesis, there is much less evidence for cyclin E2 oncogenicity.

In the first manuscript, Caldon et al. investigated the effect of breast cancer cells’ overexpression of cyclin E1 and cyclin E2 on cell cycle and genomic instability.1 Similarly to E1, overexpression of cyclin E2 resulted in chromosome aberrations, but it did not prolonged the duration of mitosis and was not associated with cdh1 or increased association with p107, which are observed with cyclin E1 overexpression. These differences suggest cyclin E1 and cyclin E2 overexpression trigger genomic instability in distinct manners, cyclin E1 possibly dependent on its ability to form complexes with cdh1 and sequester p107. It will be important to analyze cyclin E2 complexes and identify its specific interacting partners to determine how cyclin E2 overexpression promotes the genomic instability observed.

In the second paper, the authors analyzed the cell cycle-dependent abundance of cyclin E1 and cyclin E2 in cancer cells and in their normal/immortalized counterparts.2 In normal cells, cyclin E1 and E2 levels were coordinately regulated, peaking at G1/S-phase transition. However, in cancer cells cyclin E2, but not E1, levels were maintained through S-phase. This increased stability of cyclin E2 was found to be linked to failed targeting by Fbw7, a component of the Skp1-Cul1-Rbx1-Fbw7 ubiquitin ligase complex. This data may provide the molecular basis for the higher levels of cyclin E2 not correlated with cyclin E1 in cancer cells. Why Fbw7 does not recognize cyclin E2 in cancer cells, whereas it is responsible for its destruction in normal cells and is normally functional toward cyclin E1 in the same cancer cells, is still an open question. It is possible that cyclin E2 recognition by Fbw7 is impaired, possibly due a lack of appropriate phosphorylation to generate a phosphodegron or due to proteins specifically associated with overexpressed cyclin E2 that in some way regulate Fbw7 binding. This study is further evidence that the unlinked expression of these two closely related cyclins might translate to different disease outcomes.

In summary, the two reports from Caldon et al. provide novel evidence of cyclin E2 oncogenicity, underline important differences in their mechanisms of action and, finally, demonstrate that the term “cyclin E” denotes a functionally diverse family of important cell cycle regulators that contributes to the transformed phenotype.

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