Signaling Pathways in Development and Tumor Suppression

Failure to properly regulate cell differentiation and proliferation can lead to aberrant development and/or tumorigenesis. Our laboratory generates genetically modified mice to investigate the regulatory pathways that govern normal cell growth and development, and to examine how alteration of these pathways can lead to cancer. We are presently focusing on mechanisms that regulate the expression and function of tumor suppressor proteins.

Regulation of the p53 tumor suppressor by MDM proteins

The MDM2 and MDMX oncogenes are amplified and overexpressed in a wide variety of human cancers. Our previous research has demonstrated that the MDM oncoproteins complex with the p53 tumor suppressor protein and inhibit p53 functions during mouse embryogenesis. In addition to negatively regulating the p53 tumor suppressor, we have also identified p53-independent roles for Mdm2 and MdmX in governing cell proliferation and tumorigenesis. We have also explored the effects of post-translational modifications to p53 and MDM proteins to gain insight into the regulation of p53 stability and transcriptional activation. Collectively, our work has established that MDM proteins are the major regulators of the p53 tumor suppressor in normal cell growth and in development, and that alterations in MDM-p53 signaling is a common mechanistic feature in cancer. In addition, we have determined that dysregulation of p53 activity can lead to accelerated aging phenotypes in mice, linking Mdm2-p53 signaling in tumor suppression with the regulation of aging. Work to further dissect the roles of MDM proteins in regulating p53 activity in response to DNA damage and oncogene activation using knock-in mouse models is ongoing.

Non-canonical Wnt signaling in development and cancer

Wnt5a is a member of the WNT family of secreted glycoproteins that function as paracrine or autocrine signals to regulate growth control and tissue patterning. We have generated several Wnt5a mouse models to investigate the role of Wnt5a in development, and have determined that Wnt5a is required for proper gastrulation and organogenesis. In addition, we have identified a role for Wnt5a in regulation of B-cell proliferation and in suppressesing B-cell lymphomas and myeloid tumorigenesis in mice and humans. We have recently generated Wnt5a-conditional mice, and will continue to explore the role of non-canonical Wnt5a signaling in tumor suppression and in inhibiting the canonical Wnt/B-catenin signaling pathway.

Epigenetic regulation of tumor suppressor functions

Our lab has generated various other mouse models to explore epigenetic regulation of mouse development and tumorigenesis. We have documented a role of SWI/SNF chromatin remodeling in tumor suppression by deleting the Snf5 gene in mice, and revealed a functional interaction between the Snf5 and Rb tumor suppressors in cell growth and pituitary cancer. In addition, we have also recently examined the role of ING chromatin modifiers in cancer. Our studies have determined that Ing1, a member of the mSin3/HDAC complex, suppresses spontaneous follicular B-cell tumors and collaborates with p53 to prevent diffuse large B cell lymphomas. In contrast, mice deleted for Ing4 (a subunit of the HB01 HAT complex) fail to form tumors, but display defects in innate immunity due to altered NF-kB signaling. Thus ING proteins can function as tumor suppressors and/or alter inflammation in mice. Analysis of the link between inflammation and cancer in these models is ongoing. Lastly, we have also generated Dicer-conditional mice to explore the role of miRNA in the epigenetic regulation of cell growth. Loss of Dicer and miRNA biogenesis activates the p19ARF and p53 tumor suppressors and induces senescence in primary cells during development. Although ablation of Dicer can inhibit the differentiation of various cell types, deletion of Dicer in skin epithelium does not inhibit skin formation, but results in loss of fur. Interestingly, co-deletion of p53 in skin can delay the loss of fur in this model, and mice co-deleted for both p53 and Dicer develop aggressive squamous cell carcinomas. These ongoing studies indicate that miRNAs function to prevent the accumulation of DNA damage in skin epithelium and to suppress skin cancer in mice. The role of miRNAs in activating p53 functions in skin epithelium and identification of the individual miRNA molecules involved in regulating skin cancer is presently being explored.

Figures

Regulation of the p53 tumor suppressor by MDM proteins

MdmX deletion increases multi-polar mitosis resulting in rapid chromosomal loss in p53-null cells