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Mortalin-based cytoplasmic sequestration of p53 in a nonmammalian cancer model
Charles Walker1, Stefanie Böttger, Ben Low
1Department of Zoology, Center for Marine Biology and Marine Biomedical Research Group, Rudman Hall, University of New Hampshire, Durham, NH 03824, USA. cwwalker@christa.unh.edu
Abstract:
In nature the soft shell clam Mya arenaria develops a fatal neoplasm that shares molecular similarity with an unrelated group of human cancers. In leukemic clam hemocytes, wild-type p53 and mortalin proteins co-localize in the cytoplasm. A similar phenotype, characterized by cytoplasmic sequestration of wild-type p53 protein, has been observed in several human cancers (undifferentiated neuroblastoma, retinoblastoma, colorectal and hepatocellular carcinomas, and glioblastoma). In some of these cancers p53 is tethered in the cytoplasm by mortalin when the latter protein is overexpressed. Using co-immunoprecipitation we have demonstrated that mortalin and p53 proteins are complexed in the cytoplasm of leukemic clam hemocytes (and not in normal hemocytes). In addition, treatment of leukemic clam hemocytes with MKT-077, a cationic inhibitor of mortalin, disrupts the interaction of mortalin and p53 proteins, resulting in translocation of some p53 to the nucleus. Based on these data, we introduce leukemic clam hemocytes as novel and easily accessible, in vivo and in vitro models for human cancers displaying a similar mortalin-based phenotype. Treatment of these models with novel chemotherapeutics may help reveal the molecular mechanism(s) involved in inactivating p53 by this form of cytoplasmic sequestration.
Insights
Leukemic clam hemocytes exhibit a cancer-like phenotype with cytoplasmic p53 protein, similar to human cancers. This discovery offers new models for studying cancer and testing therapeutics targeting the mortalin-p53 interaction.
Area of Science:
- Comparative oncology
- Cellular and molecular biology
- Marine invertebrate pathology
Background:
- Soft shell clams (Mya arenaria) develop a fatal neoplasm.
- This clam neoplasm shares molecular similarities with human cancers.
- Cytoplasmic sequestration of wild-type p53 is a hallmark of several human cancers.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the clam neoplasm.
- To explore the potential of clam hemocytes as models for human cancer research.
- To assess the therapeutic potential of targeting the mortalin-p53 interaction.
Main Methods:
- Co-immunoprecipitation to detect protein complexes.
- Analysis of protein localization in clam hemocytes.
- In vitro and in vivo treatment with MKT-077, a mortalin inhibitor.
Main Results:
- Wild-type p53 and mortalin proteins co-localize in the cytoplasm of leukemic clam hemocytes.
- Mortalin and p53 form a complex in leukemic clam hemocytes.
- MKT-077 treatment disrupts the mortalin-p53 complex, leading to p53 nuclear translocation.
Conclusions:
- Leukemic clam hemocytes serve as accessible in vivo and in vitro models for human cancers with a mortalin-based p53 sequestration phenotype.
- These models can facilitate the study of molecular mechanisms of p53 inactivation.
- Novel chemotherapeutics targeting the mortalin-p53 interaction can be evaluated using these models.
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