Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer.
Decreased expression of the CDK inhibitor p27kip1 in human tumors directly correlates with increased resistance to chemotherapies, increased rates of metastasis, and an overall increased rate of patient mortality. It is thought that decreased p27 expression in tumors is caused by increased proteasomal turnover, in particular activation of the pathway governed by the SCFskp2 E3 ubiquitin protein ligase. We have directly tested the importance of the SCFskp-mediated degradation of p27 in tumorigenesis by analyzing the tumor susceptibility of mice that express a form of p27 that cannot be ubiquitinated and degraded by this pathway (p27T187A). In mouse models of both lung and colon cancer down-regulation of p27 promotes tumorigenesis. However, we found that preventing p27 degradation by the SCFskp2 pathway had no impact on tumor incidence or overall survival in either tumor model. Our study unveiled a previously unrecognized role for the control of p27 mRNA abundance in the development of non-small cell lung cancers. In the colon cancer model, the frequency of intestinal adenomas was similarly unaffected by the p27T187A mutation, but, unexpectedly, we found that it inhibited progression of intestinal adenomas to carcinomas. These studies may guide the choice of clinical settings in which pharmacologic inhibitors of the Skp2 pathway might be of therapeutic value.
Timmerbeul
Inke
I
Department of Gastroenterology, Hepatology, and Endocrinology, Institute for Molecular Biology, Department of Hematology and Oncology, Institute for Pathology, Hannover Medical School, D-30625 Hannover, Germany.
Garrett-Engele
Carrie M
CM
Kossatz
Uta
U
Chen
Xueyan
X
Firpo
Eduardo
E
Grünwald
Viktor
V
Kamino
Kenji
K
Wilkens
Ludwig
L
Lehmann
Ulrich
U
Buer
Jan
J
Geffers
Robert
R
Kubicka
Stefan
S
Manns
Michael P
MP
Porter
Peggy L
PL
Roberts
James M
JM
Malek
Nisar P
NP
D000818:Animals; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate; D025801:Ubiquitin / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27