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(American Journal of Pathology. 1999;154:1701-1710.)
© 1999 American Society for Investigative Pathology

Regular Articles

Analysis of Intracytoplasmic Hyaline Bodies in a Hepatocellular Carcinoma

Demonstration of p62 as Major Constituent

Cornelia Stumptner*, Hans Heid{dagger}, Andrea Fuchsbichler*, Hubert Hauser{ddagger}, Hans-Jörg Mischinger{ddagger}, Kurt Zatloukal* and Helmut Denk*

From the Departments of Pathology*
and Surgery,{ddagger}
University of Graz School of Medicine, Graz, Austria, and the Division of Cell Biology,{dagger}
German Cancer Research Center, Heidelberg, Germany

Intracytoplasmic hyaline bodies (IHBs) resemble inclusions in hepatocellular carcinoma cells, which so far have escaped further characterization. A relationship to Mallory bodies was suggested on the basis of light microscopy and filamentous ultrastructure. A hepatocellular carcinoma containing numerous IHBs was studied. Our studies revealed immunoreactivity of IHBs with the monoclonal antibodies SMI 31 and MPM-2, which recognize hyperphosphorylated epitopes present on paired helical filaments in Alzheimer's disease brains (SMI 31) or on diverse proteins hyperphosphorylated by mitotic kinases in the M-phase of the cell cycle (MPM-2). One- and two-dimensional gel electrophoresis of tumor extracts followed by immunoblotting with SMI 31 and MPM-2 antibodies revealed a major immunoreactive protein with an apparent molecular weight between 62 and 65 kd, which was resolved into several highly acidic (pH 4.5) protein components in two-dimensional gels. This protein was undetectable in non-neoplastic liver tissue. Sequence analysis identified the SMI 31 and MPM-2 immunoreactive material as p62, indicating that p62 is a major constituent of IHBs. p62 is an only recently discovered protein that is a phosphotyrosine-independent ligand of the SH2 domain of p56lck, a member of the c-src family of cytoplasmic kinases. Moreover, p62 binds ubiquitin and may act as an adapter linking ubiquitinated species to other proteins. These features suggest a role of p62 in signal transduction and possibly also carcinogenesis. IHBs observed in the hepatocellular carcinoma cells presented are the first indications of a role of p62 in disease.




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