Caveolin-1 facilitates cyclooxygenase-2 protein degradation.
Cyclooxygenase-2 (COX-2) plays major roles in diverse physiological and pathological processes such as inflammation and tumorigenesis. Transcriptional control of COX-2 has been extensively investigated and characterized, but its post-translational control is less clear. Here, we report a novel mechanism by which COX-2 is degraded. Protein levels of caveolin-1 (Cav-1) and COX-2 showed an inverse relation in colon cancer cell lines. COX-2 proteins in lung and colon tissues were higher in Cav-1 null mice than in wild-type mice. RNAi knockdown of Cav-1 increased COX-2 protein level and decreased ubiquitinated COX-2 accumulation. In addition, deletion of the carboxy (C)-terminus of COX-2, which contains a unique 19-amino acid segment compared with COX-1, resulted in reduced Cav-1 binding and attenuated COX-2 degradation. COX-1 and green fluorescence protein containing the C-terminus of COX-2 resulted in enhanced degradation. Our findings suggest that Cav-1 binds COX-2 in endoplasmic reticulum (ER) and carries it for degradation via ER associated degradation. The C-terminal region of COX-2 is required for Cav-1 binding and degradation. These results indicate a novel function of Cav-1 in controlling COX-2 expression, which may regulate physiological functions and have tumor suppression effects.
Chen
Shu-Fen
SF
Graduate School of Life Science, National Defense Medical Center, Taipei 114, Taiwan, ROC.
Liou
Jun-Yang
JY
Huang
Tai-Yu
TY
Lin
Yu-Sin
YS
Yeh
Ai-Ling
AL
Tam
Kabik
K
Tsai
Tsung-Huang
TH
Wu
Kenneth K
KK
Shyue
Song-Kun
SK
D000818:Animals; D001665:Binding Sites; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018390:Gene Targeting; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015202:Protein Engineering; D054730:Protein Interaction Domains and Motifs; D054875:Ubiquitination
D051242:Caveolin 1; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2