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Carcinogenesis Advance Access originally published online on July 7, 2004
Carcinogenesis 2004 25(11):2083-2088; doi:10.1093/carcin/bgh222
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Carcinogenesis vol.25 no.11 © Oxford University Press 2004; all rights reserved.

ARTICLE

Histone H4 histidine kinase displays the expression pattern of a liver oncodevelopmental marker

Eiling Tan1, Paul G. Besant1,2, Xin Lin Zu1, Christoph W. Turck3, Marie A. Bogoyevitch1, Seng Gee Lim4, Paul V. Attwood1 and George C. Yeoh1,2,5

1 Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia, 2 Laboratory for Cancer Medicine, The UWA Centre for Medical Research, West Australian Institute for Medical Research, Level 5, MRF Building, 50 Murray Street, Perth, WA 6000, Australia, 3 Max-Planck Institute of Psychiatry, Molecular, Cellular, Clinical Proteomics, Kraepelinstr., 2, D-80804 Munich, Germany and 4 Division of Gastroenterology, Department of Medicine, National University Hospital, 5 Lower Kent Ridge Rd, Singapore 119074

5 To whom correspondence should be addressed Email: yeoh{at}cyllene.uwa.edu.au

Protein phosphorylation is a vital process in the regulation of mammalian cell division and the protein kinases that catalyze the phosphorylation of proteins on serine, threonine and tyrosine residues have been well characterized. In contrast, little is known about the kinases involved in protein histidine phosphorylation, which have been described in various mammalian cells that are highly proliferative. Histone H4 histidine kinase (HHK) activity is highly active in regenerating rat liver. Using a novel and specific assay, we demonstrate that it is active in human fetal liver, essentially absent in adult liver and highly expressed in liver tumours. ‘Normal’ liver surrounding the HCC contains low to undetectable levels of HHK. In a rodent model of chronic liver injury that leads to HCC, its activity is induced. Two lines of evidence suggest that liver progenitor (oval) cells, which populate the liver at early stages following induction of liver damage are responsible for the increased activity. Purified oval cells, as well as cell lines established from primary cultures of oval cells express high levels of HHK. We propose that the pattern of expression of histone H4 histidine kinase activity justifies its classification as an oncodevelopmental marker and suggest it may be useful as a diagnostic marker for hepatocellular carcinoma as well for identifying preneoplastic lesions.


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Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member {gamma}, but not {alpha} or {delta}
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