Positive and negative regulation of proliferation and differentiation in tracheobronchial epithelial cells. The lung (in particular the bronchial epithelium) is a major site for tumor formation in humans. Environmental factors in conjunction with genetic factors are important determinants in this disease. The acquisition of defects in the control of proliferation and differentiation appears to constitute crucial steps in the transition of a normal to a neoplastic cell. Several factors have been identified that control positively or negatively the proliferation and differentiation of tracheobronchial epithelial cells. These factors include EGF/TGF alpha, TGF beta, insulin/IGFI, KGF, certain cytokines, retinoids, and activators of protein kinase C. Studies with neoplastic cells have identified several protooncogenes and tumor suppressor genes whose gene products are involved in the regulation of cell growth of normal tracheobronchial epithelial cells, and when mutated, lost, or activated, bring about a neoplastic phenotype. Future studies on the precise function of these genes will help to elucidate the mechanisms by which proliferation and differentiation in normal tracheobronchial epithelial cells are regulated and help to understand the molecular changes involved in diseases such as cancer. 