לוח שנה משולב

In this talk I will give an overview of how statistical mechanics may
be brought to bear on the study of populations of organisms (e.g.
microbes) that may switch between different phenotypical states. At
the microscopic level one can model the dynamics that lead to the switching on or off of certain genes. At the macroscopic level one can model how heterogeneity is maintained within a population by switching. A natural question is: what is the best switching strategy for the population in the face of a changing environment? I will focus on two simple models, one for a genetic switch with feedback and one for the growth of a population in an environment which produces catastrophic events. Both of these models may be solved exactly.

The p53 and the promeylocytic leukemia (PML) tumour suppressors network play important roles in the cellular response to stress. PML is essential for the formation of PML nuclear bodies (NBs), which have been implicated in the regulation of growth inhibition, senescence and apoptosis. We have previously shown that PML activates p53 by protecting it from Mdm2. Since PML is induced by p53 a positive loop exists between these two tumour suppressors. This loop is often interrupted in cancer cells, either by mutations in the p53 gene, and/or by downregulation of PML. We have asked whether PML also regulates mutant p53? We demonstrated a physical and functional interaction between PML and mutant p53. Surprisingly, we found that PML regulates some of the gain of function activities of mutant p53 in cancer cells lines. To define the interplay between PML and mutant p53 we extended our study to mouse models and screened human cancer patients for a correlation between PML levels and the status of p53. For this purpose we crossed PML KO mice with mice bearing the germ line p53 mutation R172H (Lang et al., 2004). We report here that PML loss enhances onset of tumourigenesis and reduces survival in the context of mutant p53.
While much has been revealed about the regulatory role of PML, the regulation of PML and the factors governing this regulation are incompletely understood. We have recently found that the mammalian E3 ligase E6AP (HPV E6 Associated Protein) promotes PML for degradation in the ubiquitin proteasome system. E6AP mediates the ubiquitination of PML in vivo and in vitro, regulates the number and intensity of PML-NBs, and affects the cellular response to genotoxic stress. Since the PML protein is downregulated in certain cancer types, we have searched for a correlation between PML and E6AP expression. An inverse correlation has been found in some cancer cell lines and human samples. To explore the role of E6AP in cancer development more directly, we employed the Eµ-Myc transgenic mouse, a model for human Burkitt’s lymphoma. We found that a loss of E6AP attenuates Eµ-Myc induced B lymphoma. This demonstrates a novel link between E6AP and tumourigenesis beyond HPV-related cancer.