Abstract
An activated Ki‐ras was expressed in the human colon adenocarcinoma cell line Caco‐2 to study the effects of Ki‐ras oncogene on polyamine metabolism during gastrointestinal tumorigenesis. Multiple clones selected for expression of the mutant Ki‐ras transgene displayed a suppression of transcription of a key catabolic enzyme in polyamine catabolism spermidine/spermine N^1^‐acetyltransferase (SSAT). Gene expression analysis, with cDNA microarrays, showed that Ki‐ras transfected clones had decreased levels of expression, compared to mock transfected cells, of peroxisome proliferator‐activated receptor gamma (PPARγ), a member of the nuclear hormone receptor family and an important regulator of cell proliferation and differentiation. The activated Ki‐ras suppressed SSAT expression by a mechanism involving the PPARγ response element (PPRE) located at +48 bp relative to the transcription start site of the SSAT gene. Transient expression of the PPARγ protein in Ki‐ras expressing Caco‐2 clones, or treatment with the PPARγ ligand ciglitazone, led to an increase in the SSAT promoter activity. A MEK1/2 inhibitor PD98059 induced transcription of both PPARγ and SSAT genes in the activated Ki‐ras clones, suggesting that the mitogen‐activated protein kinases (MAPKs) were involved in the regulation of SSAT expression by PPARγ. We concluded that mutated Ki‐ras suppressed SSAT via a transcriptional mechanism involving the PPARγ signaling pathway. © 2004 Wiley‐Liss, Inc.