The Mitogen-Activated Protein Kinase cascade operates downstream of Ras to convey cell surface signals to the nucleus via nuclear translocation of ERK1 and ERK2. We and others have recently demonstrated that activation of ERK1/2 by growth factors is required for proliferation of intestinal epithelial crypt cells. However, it remained to be established whether ERK1/2 activation alone was sufficient to trigger intestinal epithelial cell proliferation. To this aim, retrovirus encoding the HA-tagged MEK1 wild type (wtMEK), the upstream activator of ERK1/2, or a constitutive active mutant of MEK1 (MEK1-S218D/S222D, caMEK) were used to infect non immortalized human normal intestinal epithelial crypt cell cultures (HIEC) and rodent immortalized intestinal crypt cells (IEC-6). Results. 1- Stable expression of caMEK, but not wtMEK, in HIEC led to the irreversible arrest of cellular proliferation (premature senescence). Concomitant with the onset of cell cycle arrest, was the induction of the cyclin-dependent kinase inhibitors p21^Cip, p53 and p16^INK4A. 2- By contrast, overexpression of caMEK in IEC-6 cells induced growth factor relaxation for DNA synthesis, promoted morphological transformation and growth in soft agar and did not affect expression of p21^Cip, p53 and p16^INK4A. We provided evidences that ERK1b, an alternatively spliced isoform of ERK1, is activated and may contribute to the deregulation of contact inhibition cell growth and transformation of these cells. Conclusion. Constitutive activation of MEK in intestinal epithelial cells can produce either premature senescence or forced mitogenesis depending on the integrity of a senescence program controlled by the cell cycle inhibitors p53, p16^INK4A and p21^CIP.