help button home button Am J Pathol R & D Systems
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published online as doi:10.2353/ajpath.2008.070957 on June 5, 2008

Published online before print June 5, 2008
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Material
Right arrow All Versions of this Article:
ajpath.2008.070957v1
173/1/217    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Fujita, T.
Right arrow Articles by Wan, Y.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fujita, T.
Right arrow Articles by Wan, Y.
(American Journal of Pathology. 2008;173:217-228.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070957

Regulation of Skp2-p27 Axis by the Cdh1/Anaphase-Promoting Complex Pathway in Colorectal Tumorigenesis

Takeo Fujita*{dagger}, Weijun Liu*, Hiroyoshi Doihara{dagger} and Yong Wan*

From the Department of Cell Biology and Physiology,* University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and the Department of Cancer and Thoracic Surgery,{dagger} Okayama University School of Medicine, Okayama, Japan

Abrogated entry into S phase is a common hallmark of cancer cells. Skp2, a subunit of ubiquitin ligase, is critical for regulating the G1/S transition. Uncontrolled Skp2 activity is detected frequently in human tumors, often correlated with poor prognosis. Current studies have suggested that the regulation of Skp2 turnover is mediated by another critical ubiquitin ligase, the anaphase-promoting complex (APC), in association with its substrate-specific factor Cdh1. To dissect the potential role of Cdh1/APC in tumorigenesis through the degradation of Skp2, we analyzed the Cdh1/APC-Skp2-p27 axis in colorectal tumorigenesis using a human tumor array and biochemical analyses. Our results show that the percentage of Cdh1- and p27-positive samples in colon cancer tissues was significantly lower than that in adjacent nonmalignant tissue. Conversely, the percentage of Skp2-positive colon cancer samples was significantly higher than that in normal tissue. Furthermore, results from clinicopathological analysis revealed that elevated Cdh1 expression was associated with lower histological grade tumors. In addition, depletion of Cdh1 by RNA interference in nonmalignant colon cells resulted in increased cellular proliferation, whereas knockdown of Skp2 significantly suppressed cancer cell growth. Our result suggests a pathological correlation between Skp2 and Cdh1/APC in colorectal cancer. Thus, Cdh1 may function as a component in tumor suppression via proteolysis of Skp2 in colorectal tumorigenesis and may serve as a prognostic marker in colon cancer patients.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2008 by the American Society for Investigative Pathology.