Checkpoints and Cell Cycle Control Group
Previous and current research
Our research focuses on understanding the molecular mechanisms which:
- control cell growth and division and
- enable cells to respond to environmental stress and DNA damage.
By understanding these processes we hope to find ways of exploiting the mutations which occur in cancer cells for therapeutic purposes.
In recent years we have concentrated on understanding how v-Jun, an oncogene which controls gene expression, promotes cell growth and division. v-Jun deregulates cyclin E/cdk2, an important part of the cell cycle "clock" which controls the onset of DNA synthesis, and thus cell division, by inactivating the growth-inhibitory function of the Retinoblastoma (Rb) tumour suppressor protein. Remarkably, this effect of v-Jun is due, at least in part, to repression of p21CIP1/ Waf-1, a cdk2 inhibitor protein normally activated by the p53 tumour suppressor protein in response to DNA damage or certain environmental stresses.
Paradoxically, although v-Jun forces uncontrolled cell division, it also renders cells vulnerable to a form of cell suicide, termed apoptosis, when growth factors or nutrients are limiting. This is a common theme amongst oncogenes which target the cell cycle clock, and may represent a "fail-safe" mechanism designed to eliminate incipient cancer cells. v-Jun-induced apoptosis can be suppressed by certain signalling pathways and anti-apoptotic proteins which act on mitochondria, such as PI3 kinase and Bcl-2, suggesting that mitochondrial dysfunction plays an important role in triggering cell death.
Many anticancer drugs act by damaging DNA, thereby triggering a series of cell cycle "checkpoint" arrests which prevent the replication or division of damaged chromosomes. Two DNA damage-activated checkpoint effector kinases have been identified, Chk1 and Chk2, although their precise roles and targets are not yet known. We have used gene targeting to disrupt the function of Chk1 and Chk2 in DT40 tumour cells and are using the genetically modified derivatives to investigate the specific functions of these kinases and to determine whether checkpoint suppression can enhance tumour cell killing by DNA damage.
Future projects
We are currently using microarray analysis to obtain a global definition of the transcriptional basis of oncogenesis by v-Jun. This is providing new insights into the nature of cell transformation and evidence that v-Jun may also promote angiogenesis and adaptation to hypoxia. By applying microarray and proteomic analysis to Chk1- and Chk2-deficient DT40 cells we hope to identify novel targets of these kinases and obtain new insights into fundamental mechanisms of DNA damage responses.
