Aim: To examine cyclins, genes governing the cell cycle thus triggering proliferation and/or differentiation, and related genes in different steps of intestinal carcinogenesis. Patients and methods: Primary colorectal adenoma, colorectal carcinoma of various stages, adjacent normal colonic mucosa and small bowel adenocarcinoma were obtained from surgery and endoscopy. Patients had given informed consens into tissue preservation. In addition, we examined established cell lines from colorectal carcinoma and a cell line derived from intestinal epithelial cells. We further examined K-ras and cyclin D1 overexpressing derivatives of the latter cell line obtained from retroviral gene transduction. Methods of molecular biology were utilized, namely western-, northern blot analysis and polymerase-chain-reactions. To confirm the obtained results immunohistochemical studies were performed using the original tissue specimens. Results: 1) Small bowel adenocarcinomas displayed codon 12 K-ras mutations at a similiar rate as it was observed in colorectal tumors. 2) Activation of the K-ras protooncogene was followed by cyclin D1 overexpression in intestinal epithelial cells. 3) In colorectal carcinoma, the G1-phase cyclin D1 and E displayed an increased mRNA- and protein expression. 4) In intestinal epithelial cells, constitutive overexpression of cyclin D1 did neither alter growth properties in vitro nor resulted in tumorigenicity of cyclin D1 overexpressing derivatives of these cells. 5) Relative overexpression of cyclin E proteins was observed in an important fraction of colorectal carcinoma when compared to adjacent normal colonic mucosa. In contrast, cyclin E overexpression could not be detected in any colorectal adenoma examined, and this was closely related to the transformation step of colorectal epithelial cells. 6) No relationship between cyclin E protein- and mRNA- expressions could be detected. 7) In colorectal carcinoma, we could demonstrate a relationship between a relatively increased and/or aberrant cyclin E protein expression compared to normal mucosa and a mutator-phenotype of the carcinoma examined. Conclusion: In colorectal tumors, cyclin D1 overexpression partially results from activated K-ras protooncogenes during the earlier steps of colorectal carcinogenesis. In this context, cyclin D1 does not act as an oncogene itself. In contrast, overexpression of cyclin E may support the transformation of colorectal epithelial cells. The relative abundancy of cyclin E proteins might hinder DNA replication processes and thus enhance the effect of a deficient DNA repair system.