p27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells

  1. Siva Kumar Kolluri,
  2. Carsten Weiss,
  3. Andrew Koff, and
  4. Martin Göttlicher
  1. Forschungszentrum Karlsruhe, Institute of Genetics, 76021 Karlsruhe, Germany; Laboratory of Cell Cycle Regulation, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 USA

Abstract

The Ah receptor (AhR), a bHLH/PAS transcription factor, mediates dioxin toxicity in the immune system, skin, testis and liver. Toxic phenomena are associated with altered cell proliferation or differentiation, but signaling pathways of AhR in cell cycle regulation are poorly understood. Here we show that AhR induces the p27Kip1 cyclin/cdk inhibitor by alteringKip1 transcription in a direct mode without the need for ongoing protein synthesis or cell proliferation. This is the first example of Kip1 being a direct transcriptional target of a toxic agent that affects cell proliferation. Kip1 causes dioxin-induced suppression of 5L hepatoma cell proliferation because Kip1antisense-expressing cells are resistant to dioxins. Kip1 is also induced by dioxins in cultures of fetal thymus glands concomitant with inhibition of proliferation and severe reduction of thymocyte recovery.Kip1 expression is likely to mediate these effects as thymic glands of Kip1-deficient mice (Kip1Δ51 ) are largely, though not completely, resistant.

Keywords

Footnotes

  • These authors contributed equally to this work.

  • Corresponding author.

  • E-MAIL martin.goettlicher{at}igen.fzk.de; FAX 49-7247-82-3354.

    • Received January 25, 1999.
    • Accepted May 18, 1999.
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