Laboratory of Carl Maki, PhD


Carl Maki, PhD

Carl Maki, PhD, is an associate professor in the Department of Cell & Molecular Medicine. He earned his bachelor’s degree in biology in 1987 from the University of Wisconsin Lacrosse and his PhD in 1993 from Kansas State University. Maki received post-doctoral training in cancer biology at the National Institutes of Health and Harvard Medical School. He has held faculty positions at the Harvard School of Public Health, the University of Chicago and Rush University.

Our research

P53 is a tumor suppressor and potent cell growth inhibitor. Wild-type p53 is expressed at low levels in most cells. However, p53 levels increase, and the protein is activated in response to DNA damage and other stresses. Activated p53 then inhibits growth or induces cell death.

Mutations in the P53 gene are the most common genetic change in cancer. These mutations inhibit the ability of p53 to respond to cancer-causing stresses. Our lab is examining how p53 is regulated normally, and how this regulation is altered in cancer.

P53 affects cancer cell metabolism and autophagy

P53A long-standing paradigm was that tumor suppression by p53 resulted from activation of genes that promote cell cycle arrest or apoptosis. However, recent studies have shown p53 can alter cancer cell metabolism and autophagy, and both effects may contribute to tumor suppression.

We are studying how metabolism and autophagy are linked in the cellular response to p53 activation. An article describing these results can be found here: Duan L, Perez RE, Davaadelger B, Dedkova EN, Blatter LA, Maki CG. (September 15, 2015.) “p53-Regulated Autophagy Is Controlled by Glycolysis and Determines Cell Fate.Oncotarget.6(27):23135-5

Nutlin-3a is a p53 activator

human lung cancer cellsP53 is expressed at low levels in most cells due to MDM2, an E3 ligase that binds p53 protein and promotes its degradation. Small-molecule inhibitors of p53-MDM2 (e.g., Nutlin-3a) are being developed as therapeutic agents. These molecules disrupt p53-MDM2 binding in p53 wild-type cancer cells, thus unleashing p53 to inhibit proliferation and induce death. We are studying how normal and cancer cells respond to MDM2 antagonists like Nutlin-3a, with the hope of increasing their therapeutic potential in cancer.

In this picture human lung cancer cells were untreated (top right) or treated with Nutlin-3a (bottom right) to activate wild-type p53. Cytoskeleton proteins were visualized by immunostaining. The results show that Nutlin-3a alters the cancer cell cytoskeleton. This resulted in decreased ability of these cancer cells to migrate. See this publication: “Nutlin-3a Induces Cytoskeletal Rearrangement and Inhibits the Migration and Invasion Capacity of p53 Wild-Type Cancer Cells.
Moran DM, Maki CG.
Mol Cancer Ther. 2010 Apr;9(4):895-905. doi: 10.1158/1535-7163.MCT-09-1220. Epub 2010 Apr 6

Grants

NIH 5R21CA178733 (PI):  “Modeling the Etiology of p53 Mutated Cancer Cells”

NIH 5R21CA185036 (PI):  “Identification and Targeting Therapy resistant Osteosarcoma”

NIH 1R01CA200232 (PI):  “Targeting Prolyl Peptidases in Tamoxifen Resistant Breast Cancer”

DoD W81XWH-16-1-0025 (PI):  “Targeting Prolyl Peptidases in Triple-Negative Breast Cancer”

Carl Maki Lab members

Lab members 2016

Publications

A complete listing of Maki’s publication can be found on PubMed.

Contact

Carl Maki, PhD
Associate Professor
Department of Cell & Molecular Medicine