Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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A Distinct Domain of Mcl1 Regulates Senescence Inhibition in Cancer
Abeba Demelash, PhD1, Lukas W. Pfannenstiel, PhD2, Brian T. Maybruck, PhD2, Simon E. Schlanger, BS2, Tannenbaum S. Charles, PhD2, Brian R. Gastman, MD2.
1Institutes of Head and Neck, Dermatology and Plastic Surgery, Taussing Cancer Center and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Cleveland, OH, USA, 2Institutes of Head and Neck, Dermatology and Plastic Surgery, Taussing Cancer Center and Lerner Research Institute, Cleveland, OH, USA.

PURPOSE:
Myeloid cell leukemia (Mcl1) protein differs from its anti-apoptotic BCL-2 family members in its large size of 350 residues and extended, non-homologous, regulatory domain-containing N-terminus. We have recently demonstrated that Mcl1 plays an important role in tumor progression through the inhibition of chemotherapy-induced senescence in colon cancer. In the present study, we focused our attention on investigating a distinct domain within Mcl1 responsible for its anti-senescence properties in several colon cancer cell lines.
METHODS:
This has been addressed by generating several deletion mutants of Mcl1, and then assessing the sub cellular distribution, extent of senescence inhibition, and occurrence of DNA damage in response to chemotherapy.
RESULTS:
We observed that re-expression of a set of Mcl1-N and C-terminal deletion mutants into Mcl1 deficient cells resulted in the accumulation of these mutant proteins in the nucleus. This is in stark contrast to most of its known functions epicentered in the mitochondria. These mutants included those that had deletions of all known functional aspects of the molecule and were nonetheless able to inhibit senescence similar to wild type Mcl1, and resulted in substantial increases in BrdU uptake, reduction in the percentage of senescence-associated beta-galactosidase positive cells, PML and γH2AX foci formation after drug treatment. In addition use of both deletion mutants and substitution mutants of several phosphorylation sites revealed that two of the most important post-translational N-terminal regulation modalities of Mcl-1 were dispensable for its anti-senescence functions.Based on this data, we then developed more specific mutants and identified an internal domain within Mcl-1 key to its senescence function. Specifically residues 198-207 appear to be key in Mcl1’s senescence modulation, as cell expressing the Mcl1 ∆198-207 deletion mutant where not protected against drug-induced senescence.
CONCLUSION:
Taken together, this study indicates that a newly discovered domain within Mcl-1, through nuclear events is responsible for its anti-senescence properties in cancer cells.


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