Attenuation of proteolysis-mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers.
Parkin has a critical role in the ubiquitin-proteasome system as an E3-ligase targeting several substrates. Our recent finding that Parkin-deficient mice are susceptible to tumorigenesis provided evidence that Parkin is a tumor suppressor gene. Dysfunction of the Parkin gene is frequently observed in various human cancers, but the mechanism underlying the cell cycle disruption induced by Parkin dysfunction that leads to carcinogenesis is not known. Here, we demonstrated that Parkin expression in colonic epithelial cells is regulated in a cell cycle-associated manner. Epidermal growth factor (EGF) stimulation upregulated Parkin gene expression in human colon cells. Inhibition of the phosphoinositide 3-kinase [PI(3)K]-Akt-dependent pathways suppressed growth factor-induced Parkin expression. The expression of alternatively spliced Parkin isoforms with various deletions spanning exons 3-6 was detected in 18 of 43 (42%) human colorectal cancer tissues. Wild-type Parkin induced the degradation of cyclin E protein, but the alternatively spliced Parkin identified in colon cancers showed defective proteolysis of cyclin E. These findings indicate that Parkin expression is induced by growth factor stimulation and is involved in the cell cycle regulation of colon cells. Tumor-specific expression of alternatively spliced Parkin isoforms might contribute to enhanced cell proliferation through the attenuation of proteolysis-mediated cyclin E regulation in human colorectal cancers.
Ikeuchi
Kyoko
K
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Marusawa
Hiroyuki
H
Fujiwara
Mikio
M
Matsumoto
Yuko
Y
Endo
Yoko
Y
Watanabe
Tomohiro
T
Iwai
Akio
A
Sakai
Yoshiharu
Y
Takahashi
Ryosuke
R
Chiba
Tsutomu
T
D017398:Alternative Splicing; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D019927:Cyclin E; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D051057:Proto-Oncogene Proteins c-akt