Cyclin E deregulation leads to genomic instability independently of cyclin-dependent kinase activity.
How do genomic instability and chromosomal instability contribute to tumorigenesis? Bruce Clurman, Piotr Sicinski and colleagues report the surprising finding that cyclin E, which, when deregulated, is associated with genomic instability, might mediate its essential and oncogenic functions independently of cyclin-dependent kinase (CDK) activity. And Don Cleveland and colleagues have used a centromere-associated protein-E (CENPE) haploinsufficient mouse model to dissect the contribution of chromosomal instability to tumorigenesis.
Cyclin E deregulation induces genomic instability as an early event in tumorgenesis, and is thought to directly contribute to the loss of TP53 heterozygosity in many cancer types. When cyclin E is overexpressed, the loading of the minichromosome maintenance (MCM) protein complexes onto DNA replication origins is defective, and could account for the induction of genomic instability. However, the precise function of cyclin E in DNA replication licensing and tumorigenesis remains unclear. Sicinski, Clurman and colleagues showed that exogenous expression of a cyclin E1 mutant that cannot activate the associated CDK (cyclin E1-kinase-deficient (KD)) in murine embryonic fibroblasts (MEFs) derived from mice that lacked cyclin E1 and cyclin E2 (encoded by Ccne1 and Ccne2) restored both the ability of these MEFs to re-enter the cell cycle from senescence and their susceptibility to oncogenic RasV12-induced transformation. Cyclin E1-KD behaved like wild-type cyclin E1, and allowed the incorporation of MCM2 onto chromatin. Furthermore, the authors showed that both cyclin E1-KD and wild-type cyclin E1 interact with CDT1, MCM2 and MCM7 to mediate DNA replication licensing in human cells. These CDK-independent functions of cyclin E1 potentially account for its essential role in G1–S progression and its ability to induce oncogenic genomic instability. This is particularly interesting given that small-molecule CDK inhibitors are being examined as anticancer therapeutics.
Genomic instability actively contributes to tumorigenesis. Whether chromosomal instability, specifically aneuploidy (whole chromosome gains and losses), also has an active role or is a benign side-effect has remained controversial. CENPE is an essential member of the mitotic-spindle checkpoint that serves to ensure the accurate segregation of sister chromatids. Cleveland and colleagues showed that near diploid aneuploidy increased with age in vitro in Cenpe+/- MEFs and in vivo in lymphocytes, splenocytes and colon cells. Importantly, increased aneuploidy did not cause chromosomal rearrangements or DNA damage, showing that aneuploidy was induced in the absence of other defects (such as genomic instability). Aged Cenpe+/- animals developed an increased level of lymphomas of the spleen and adenomas of the lung, consistent with the hypothesis that aneuploidy drives tumorigenesis. Surprisingly, however, Cenpe+/- mice developed fewer spontaneous liver tumours. In addition, Cenpe+/- mice were more resistant to chemically induced tumorigenesis, and the latency of tumours in tumour-prone Arf-;/- mice was extended by Cenpe heterozygosity. Therefore, whether aneuploidy functions as a tumour suppressor or is oncogenic seems to be determined by the cellular context. In this case, the rate of chromosome gain and loss might be crucial, with slower changes in chromosome number promoting tumorigenesis and more rapid changes leading to cell death and tumour suppression.
These reports provide significant advances in our understanding of the molecular biology of tumorigenesis. Indeed, the nuances between genomic instability and chromosomal instability and their influence on tumorigenesis are of interest, particularly in terms of identifying the cancer-type-specific activities and pathways that might, or might not, provide clinically viable targets for anticancer drug development.
Gemma Alderton
References
Geng, Y. et al. Kinase-independent function of cyclin E. Mol. Cell25, 127–139 (2007) | Article | PubMed |
Weaver, B. A. A. et al. Aneuploidy acts both oncogenically and as a tumour suppressor. Cancer Cell11, 25–36 (2007) | Article | PubMed |
Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell11, 9–23 (2007) | Article | PubMed |
