Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 21, Pages 14700-14710Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M602623200
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Funding
- NCI NIH HHS [R01 CA 118992] Funding Source: Medline
- NIDDK NIH HHS [F32 DK 67812] Funding Source: Medline
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Peroxisome proliferators-activated receptor gamma(PPAR gamma) has been shown to suppress cell proliferation and tumorigenesis, whereas the gastrointestinal regulatory peptide gastrin stimulates the growth of neoplastic cells. The present studies were directed to determine whether changes in PPAR gamma expression might mediate the effects of gastrin on the proliferation of colorectal cancer (CRC). Initially, using growth assays, we determined that the human CRC cell line DLD-1 expressed both functional PPAR gamma and gastrin receptors. Amidated gastrin (G-17) attenuated the growth suppressing effects of PPAR gamma by decreasing PPAR gamma activity and total protein expression, in part through an increase in the rate of proteasomal degradation. G-17-induced degradation of PPAR gamma appeared to be mediated through phosphorylation of PPAR gamma at serine 84 by a process involving the biphasic phosphorylation of ERK1/2 and activation of the epidermal growth factor receptor (EGFR). These results were confirmed through the use of EGFR antagonist AG1478 and MEK1 inhibitor PD98059. Furthermore, mutation of PPAR gamma at serine 84 reduced the effects of G-17, as evident by inability of G-17 to attenuate PPAR gamma promoter activity, degrade PPAR gamma, or inhibit the growth suppressing effects of PPAR gamma. The results of these studies demonstrate that the trophic properties of gastrin in CRC may be mediated in part by transactivation of the EGFR and phosphorylation of ERK1/2, leading to degradation of PPAR alpha protein and a decrease in PPAR alpha activation.
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