The overall goal of the work performed in my laboratory is to define how cancer cells exploit mechanisms that regulate normal cell division in order to survive and proliferate. Normal cell cycle phase transitions are carefully regulated by multiple, partially redundant mechanisms; however, loss of function of several key tumor suppressor pathways that regulate cell cycle progression occurs in virtually all cancer cells. Among these pathways are those controlled by the Retinoblastoma (Rb) and p53 tumor suppressor proteins. The Rb pathway controls cell cycle progression from G1-to-S phases. Negative regulators of this pathway include the INK4 and Cip/Kip proteins; positive regulators include the cyclins and cyclin-dependent kinases (Cdks). p53 is a master regulator of multiple cell cycle checkpoints and cell survival, and it is activated by post-translational modifications in response to DNA damage.
Cyclin E, which positively regulates S-phase entry, is a major focus of our studies. It is frequently over-expressed in cancer cells (often via impaired degradation caused by loss-of-function mutations in the E3 ubiquitin ligase protein, Fbw7), and cyclin E over-expression may promote further acquisition of malignant properties due to production of genome instability. Cyclin E-associated genome instability is dependent on loss of p53, which is able to inhibit cyclin E/Cdk2 activity via the induction of p21Cip1. Despite its link to genome instability, how cyclin E overexpression promotes cancer remains unclear. Does cyclin E overexpression in cancer cells signify particular biological properties or does it more often only indicate loss of Rb pathway control? Is p53-loss absolutely required for deregulated cyclin E to promote tumors? What are other collaborating events in cyclin E-associated tumorigenesis? These are key questions we are addressing in my laboratory.
In addition to its role in promoting genome instability, we have found that cyclin E, when deregulated, is able to promote cellular hyper-proliferation in vivo. Specific cell lineages seem to be especially vulnerable to the consequences of deregulated cyclin E activity. Using a novel mouse knockin model to study the physiologic consequences of impaired Fbw7-mediated cyclin E degradation, we found that deregulated cyclin E produces multiple abnormalities in erythroid progenitors, including greatly increased proliferation, impaired maturation, increased apoptosis, and dysplastic morphologies. We see similar evidence of increased proliferation, counter-balanced by increased apoptosis, in mammary epithelial cells as well. In ongoing studies, we are elucidating the basis of this cell-type specificity in the physiologic responses to deregulated cyclin E. In addition to cancer models we are developing, we are also elucidating the mechanisms by which increased cyclin E activity promotes defective erythroid maturation in vivo. A long-term goal of our research is to determine whether these mechanisms are involved in the pathogenesis of human hematopoietic diseases, such as myelodysplasia and leukemia.
Publications:
Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney B, Bernstein ID, Roberts JM, and Clurman BE. Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes and Development; in press.
Minella AC, Grim JE, Welcker M, and Clurman BE. Fbw7 and p53 cooperatively restrain cyclin E-associated genome instability. Oncogene 2007; 26: 6948-53.
Minella AC, Welcker M, and Clurman BE. Ras activity regulates cyclin E degradation by the Fbw7 pathway. Proceedings of the National Academy of Sciences 2005; 102: 9649-54.
Minella AC, Swanger J, Bryant E, Welcker M, Hwang HC, and Clurman BE. p53 and p21 form an inducible barrier that protects cells against cyclin E-cdk2 deregulation. Current Biology 2002; 12: 1817-1827.
