Am. Lefrancoismartinez et al., GLUCOSE-DEPENDENT REGULATION OF THE L-PYRUVATE KINASE GENE IN A HEPATOMA-CELL LINE IS INDEPENDENT OF INSULIN AND CYCLIC-AMP, The FASEB journal, 8(1), 1994, pp. 89-96
Hepatocyte-like mhAT3F cells have been derived from the hepatoma of a
transgenic mouse expressing the SV40 large T antigen under the control
of the antithrombin III gene regulatory region (Antoine, B., Levrat,
F., Vallet, V., Berbar, T., Cartier, N., Dubois, N., Briand, P., and K
ahn, A. (1992) Gene expression in hepatocyte-like lines established by
targeted carcinogenesis in transgenic mice. Exp. Cell. Res. 200, 175-
185; F. Levrat et al., unpublished results). In these cells, the L-PK
gene is transcriptionally activated by glucose, as it is in vivo and i
n cultured hepatocytes. However, in contrast to the L-PK gene regulati
on in the liver and isolated hepatocytes, the glucose responsiveness d
oes not require insulin and is not blocked by cyclic AMP. In mhAT3F ce
lls, the insensitivity to insulin might be due to the replacement of i
nsulin-dependent glucokinase by insulin-independent hexokinases able t
o phosphorylate glucose in the absence of the hormone. The glucose-dep
endent activation of the L-PK gene is delayed, requires ongoing protei
n synthesis, and is mediated by the same glucose response element as i
n vivo and in isolated hepatocytes. These results suggest that the glu
cose-dependent signaling pathway responsible for the transcriptional a
ctivation of glycolytic and lipogenic genes requires glucose phosphory
lation, a phenomenon that is insulin-dependent in the liver but insuli
n-independent in cultured hepatoma cells. Nevertheless, the action of
glucose 6-phosphate is most likely indirect.