Hepatitis B virus-related insertional mutagenesis implicates SERCA1 gene in the control of apoptosis

We have used the Hepatitis B Virus DIVA genome as a probe to identify genes clonally mutated in vivo, in human liver cancers. In a tumor, HBV-DNA mas found to be integrated into the gene encoding Sarco/Endoplasmic Reticulum C alcium ATPase (SERCA), which pumps calcium, an important intracellular mess enger for cell viability and growth, from the cytosol to the endoplasmic re ticulum. The HBV X gene promoter cis-activates chimeric HBV X/SERCA1 transc ripts, with splicing of SERCA1 exon II, encoding C-terminally truncated SER CA1 proteins. Two chimeric HBV X/SERCA1 proteins accumulate in the tumor an d form dimers. III vitro analyses have demonstrated that these proteins loc alize to the ER, determine its calcium depletion and induce cell death. We have also shown that these biological effects are related to expression of the SERCA, rather than of the viral moiety. This report involves for the fi rst time the expression of mutated SERCA proteins in vivo in a tumor cell p roliferation and in vitro in the control of cell viability.