Mortalin-based cytoplasmic sequestration of p53 in a nonmammalian cancer model.
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.
Walker
Charles
C
Department 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
Böttger
Stefanie
S
Low
Ben
B
D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006434:Hemocytes / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007938:Leukemia / Q000378:metabolism; D008969:Molecular Sequence Data; D049892:Mya; D009369:Neoplasms / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D013347:Subcellular Fractions; D013844:Thiazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D011725:Pyridines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C080352:mortalin; C097880:MKT 077