Hox gene products, initially characterized as master regulators of embryonic patterning, are also required for proper functioning of adult tissues. There is also a growing body of evidence that links Hox proteins to regulation of cellular proliferation/transformation. However, the underlying molecular mechanisms of Hox-associated transformation and tissue growth have yet to be elucidated. Using a well established model system for studying changes in cellular proliferation induced by Hoxb4, we show that AP-1 activity is markedly increased in Hoxb4-transduced cells due to significant upregulation of Jun-B and Fra-1 protein levels. Furthermore, we also show that the specific changes in AP-1 protein expression are necessary for the proliferation effects induced by Hoxb4, and that these changes converge to increase levels of cyclin D1, a known integrator of proliferation signals. Our observations thus link Hox gene products with key elements of the cell cycle machinery.