Translation control of tumor suppressor protein p27Kip1 in normal and cancer cells.
p27 is an inhibitor of cell cycle progression that is commonly down-regulated in cancer cells. Low levels of p27Kip1 expression are correlated with poor prognosis for many types of cancer. Our lab has discovered a novel mechanism of translational control that may govern synthesis of this protein. This involves regulatory sequences in the 5’-untranslated region of the mRNA that encodes p27Kip1.The goal of our research is to determine the mechanisms by which the p27Kip1 5’-UTR is used for initiating cap-independent translation. We have identified a series of RNA-binding proteins that modulate this activity. We are determining how these proteins are regulated and how they influence recruitment of the small ribosomal subunit during initiation. We have found that cap-independent translation of p27Kip1 is highly variable in breast cancer cells and that this correlates with endogenous p27Kip1 protein levels. We are analyzing the process of cap-independent translation and how this varies between various breast cancer cells.
Metabolism, mitochondria, and cell death mechanisms in breast cancer, ovarian cancer and HNSCC.
Another research interest in our laboratory is tumor cell metabolism. Cancer cells undergo a process called metabolic reprogramming that allows them to survive and proliferate under conditions that would be detrimental to normal cells. By modulating the altered metabolic processes, it may be possible to specifically target cancer cells and inhibit their growth and promote their death. We have found that several drugs or compounds that alter specific metabolic pathways are toxic to cancer cells. One of these drugs is metformin, which is commonly used for treating type II diabetes. In cancer cells, metformin inhibits cell proliferation and then promotes cell death. We are analyzing the mechanisms that lead to these cellular responses. Our goal is to determine the molecular pathways that mediate these effects. We are also identifying other metabolism-targeted drugs and compounds that synergize with metformin to kill cancer cells.
Contact Information for Miskimins Lab:
W. Keith Miskimins, PhD