Transcriptional and post-transcriptional regulation of the asialoglycoprotein receptor in normal and neoplastic rat liver.

We have previously shown that immunologically detectable cell surface asialoglycoprotein (ASGP) receptors are decreased or absent in proliferating in vivo hepatocytes, such as in developing, regenerating, preneoplastic, and neoplastic liver samples. We now show that this decrease is the result of a post-transcriptional mechanism(s), since specific ASGP receptor transcripts are quantitatively unaltered in the above samples based on Northern blot analysis using a specific cDNA ASGP receptor probe. In primary hepatomas, the major, minor, or both ASGP receptor transcripts are translated into functional protein since specific binding of I125 asialoorsomucoid to total hepatoma homogenates is identical to normal liver. However, Western blot analysis using a polyclonal antibody directed against the ASGP receptor indicated that peptides corresponding to RHL-2 and RHL-3 are present at increased levels in the cytosol fraction of primary hepatoma cells, whereas the RHL-1 species is not detectable in either the plasma membrane, microsomal, or cytosol fractions of these cells. We also show that ASGP receptor activity can be modulated by transcriptional mechanisms, since primary rat hepatocytes cultured for 24 h have decreased ASGP receptor transcripts. In addition, Morris hepatoma 7777 cells, either in culture or growing as a transplantable tumor in vivo, have no detectable ASGP receptor transcripts, while still retaining the ASGP receptor gene.