Researchers
Lindsey D. Mayo, PhD Assistant Professor: Department of Pediatrics
Assistant Professor: Department of Pediatrics
Clinical Section: Pediatric Hematology/Oncology
Faculty: Assistant Professor, Departments of Radiation Oncology and Pharmacology, Case Western Reserve University and the Case Comprehensive Cancer Center.
Postdoctoral Fellowship: Department of Microbiology and Immunology, Indiana; University School of Medicine and the Walther Oncology Center
PhD: Wright State University, Dayton, Ohio
E-mail: ldmayo@iupui.edu
Current Research Interests:
To elucidate the biochemical mechanisms that control tumor suppressors and oncoproteins to induce or restrict tumor progression and metastasis.
Research:
The focus of Dr. Mayo's laboratory is to define the modifications to key tumor suppressor proteins, and oncoproteins that alter their respective activity to either disrupt or contribute to tumor progression. Hdm2 protein is frequently detected in breast, prostate, brain cervix, testicular, pancreatic, and ovarian cancers as well as melanomas, osteosarcomas, and leukemia and lymphomas. The detection of the Hdm2 oncoprotein is correlated with highly aggressive late stage cancer with a poor prognosis. What is not known is how Hdm2 is upregulated at this late stage or in recurrent disease. The understanding of the mechanisms involved in inducing the levels Hdm2 is a central project in the laboratory. Hdm2 has been characterized as an E3 ubiquitin ligase, and an Ubiquitin like ligase. One substrate of Hdm2 is the tumor suppressor protein, p53. Hdm2 can bind to p53 and inactivate p53's transcriptional activity and target p53 for destabilization or inactivating stabilization. The precise mechanism and stimulus of how Hdm2 regulates p53 stability is largely not well understood. Our work has shown how Hdm2's ability to regulate p53 and other proteins to induce tumor proliferation is dictated by its ability to gain nuclear entry, which is mediated by signal transduction pathways that are hyperactivated in cancer. Hdm2 function in regulating p53 dependent and independent mechanisms in cancer progression and the importance of Hdm2 activity is regulated as an E3 ligase and how it influences cellular processes to promote tumor progression is ongoing work in the laboratory.
The PTEN tumor suppressor opposes the signaling pathway that mediates Hdm2 nuclear entry and thereby protects p53 transcriptional activity by sequestering Hdm2 in the cytoplasm. Our work has defined the distinct signal transduction pathways that promote p53 to either induce the Hdm2 gene, or the PTEN gene in response to the severity of the DNA damage caused by chemotherapeutic drugs. Dependent on severity of the DNA damage and the downstream signals to p53, p53 may preferentially induce different genes whose gene products mediate program cell death or survival. Our work shows that the tumor cells the intactness of the p53-PTEN pathway is necessary in order to undergo significant cell death. Further work is underway to investigate how the high dosing of chemotherapy influences the activation of PTEN as a tumor suppressor in coordination with p53.
