Suppression of polyamine catabolism by activated Ki-ras in human colon cancer cells.
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 N1-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 (PPARgamma), 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 PPARgamma response element (PPRE) located at +48 bp relative to the transcription start site of the SSAT gene. Transient expression of the PPARgamma protein in Ki-ras expressing Caco-2 clones, or treatment with the PPARgamma ligand ciglitazone, led to an increase in the SSAT promoter activity. A MEK1/2 inhibitor PD98059 induced transcription of both PPARgamma 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 PPARgamma. We concluded that mutated Ki-ras suppressed SSAT via a transcriptional mechanism involving the PPARgamma signaling pathway.
Ignatenko
Natalia A
NA
Department of Cell Biology, Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.
Babbar
Naveen
N
Mehta
Dipti
D
Casero
Robert A
RA
Gerner
Eugene W
EW
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D018938:Caco-2 Cells; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D011073:Polyamines / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D020928:Mitogen-Activated Protein Kinases; D011073:Polyamines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D018631:ras Proteins; D000099228:Diamine N-Acetyltransferase