Research summary

Carcinogens induce growth inhibition of normal cells, whereas initiated cells and preneoplastic lesions escape this effect and thus achieve a growth advantage. A model predicts that DNA-damaging carcinogens inhibit proliferation through induction of p53 and subsequently p21CIP.

In previous research we have found that carcinogen exposure inhibits Erk1/2 nuclear translocation, but not phosphorylation. In addition, Cdk2 and Cdk4 became cytoplasmically arrested in carcinogen-exposed hepatocytes. Since p21CIP binding to Cdk2 and Cdk4 complexes were not increased, we hypo-thesized that p53 induction was not the mechanism of carcinogen mitoinhibition.

To further clarify these mechanisms we seeked a closer knowledge of the intracellular signalling transforming growth factor binding in the plasma membrane to transcript-tional activation initiating DNA synthesis.

We currently complete several studies:

• A manuscript showing that nuclear translocation of Erk1/2 is accomplished by MEK1, whereas MEK2 promotes cytoplasmic retention, has been submitted. Phosphorylations of MEK1 S292/S298 induce the release Erl1/2 from MEK1, and thus nuclear translocation. This phosphorylation depends upon Rac1-activation; probably reflecting integrin signalling.
• We now publish that p53 is growth factor induced, and plays an important role inthe proliferation of normal hepatocytes. When p53 induction is inhibited, the cellsbecome growth arrested, and Cdk2 and Cdk4 remain cytoplasmically arrested. These effects are counteracted by ectopic expression of p21CIP, which may provide a piggy-backing NLS signal to G1 Cdk complexes.
• Furthermore, we have submitted a manuscript showing that Cdk4 activation is necessary for subsequent Cdk2 nuclear translocation and proliferation.
• We currently publish that H-Ras and K-Ras are differentially involved in growth factor signalling of hepatocytes. Whereas H-Ras activates Erk1/2 and PI3K, thus promoting both proliferation and survival, K-Ras activation promotes survival through PI3K activation.
• Based on a grant from the Research Council of Norway we have initiated a study on the mechanisms of non-dioxin-like PCB toxicity. Initial studies show that PCB153 enhances the EGF-induced proliferation, possibly through shortened G1 phase. Involved mechanisms will be investigated in further studies.
• Two PhD students are in the final stages of their doctoral projects, and submitted their theses early 2007.
• Based on a grant from the Research Council of Norway, a confocal microscope configured for live cell imaging has been installed. The microscope has been made available for scientists at Gaustad campus through our core facility.