p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells

The Ah receptor (AhR), a bHLH/PAS transcription factor, mediates dioxin tox icity in the immune system, skin, testis and liver. Toxic phenomena are ass ociated with altered cell proliferation or differentiation, but signaling p athways of AhR in cell cycle regulation are poorly understood. Here we show that AhR induces the p27(Kip1) cyclin/cdk inhibitor by altering Kip1 trans cription in a direct mode without the need for ongoing protein synthesis or cell proliferation. This is the first example of Kip1 being a direct trans criptional target of a toxic agent that affects cell proliferation. Kip1 ca uses dioxin-induced suppression of 5L hepatoma cell proliferation because K ip1 antisense-expressing cells are resistant to dioxins. Kip1 is also induc ed by dioxins in cultures of fetal thymus glands concomitant with inhibitio n of proliferation and severe reduction of thymocyte recovery. Kip1 express ion is likely to mediate these effects as thymic glands of Kip1-deficient m ice (Kip1(Delta 51)) are largely, though not completely, resistant.