TY - JOUR
T1 - An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant
AU - Ji, Peng
AU - Jiang, Hong
AU - Rekhtman, Katya
AU - Bloom, Joanna
AU - Ichetovkin, Marina
AU - Pagano, Michele
AU - Zhu, Liang
N1 - Funding Information:
We thank E. Harlow, F. Kaye, T. Jacks, W. Kaelin, A. Follenzi, L. Naldini, Z.-Q. Pan, W. Sellers, E. R. Stanley, S. Dowdy, T. Shenk, Y. Xiong, and H. Zhang for providing the various reagents used in this study. We thank P. Lu for lentivirus vector construction; I. Basu with ubiquitination assay conditions; and A. Karnezis, X. Wang, and other members of our laboratory for helpful discussion. This work was supported by grants from the American Cancer Society and the National Institutes of Health (NCI, NIDDK, and NGM). Albert Einstein Comprehensive Cancer Research Center Grant provided support for FACS and other core facilities. K.R. was a trainee of the Einstein Medical Scientists Training Program. L.Z. is a Leukemia and Lymphoma Society Scholar.
PY - 2004/10/8
Y1 - 2004/10/8
N2 - It is believed that Rb blocks G1-S transition by inhibiting expression of E2F regulated genes. Here, we report that the effects of E2F repression lag behind the onset of G1 cell cycle arrest in timed Rb reexpression experiments. In comparison, kinase inhibitor p27Kip1 protein accumulates with a faster kinetics. Conversely, Rb knockout leads to faster p27 degradation. Rb interacts with the N terminus of Skp2, interferes with Skp2-p27 interaction, and inhibits ubiquitination of p27. Disruption of p27 function or expression of the Skp2 N terminus prevents Rb from causing G1 arrest. A full-penetrance, inactive Rb mutant fails to interfere with Skp2-p27 interaction but, interestingly, a partial-penetrance Rb mutant that is defective for E2F binding retains full activity in inhibiting Skp2-p27 interaction and can induce G1 cell cycle arrest with wild-type kinetics. These results identify an Rb-Skp2-p27 pathway in Rb function, which may be involved in inhibition of tumor progression.
AB - It is believed that Rb blocks G1-S transition by inhibiting expression of E2F regulated genes. Here, we report that the effects of E2F repression lag behind the onset of G1 cell cycle arrest in timed Rb reexpression experiments. In comparison, kinase inhibitor p27Kip1 protein accumulates with a faster kinetics. Conversely, Rb knockout leads to faster p27 degradation. Rb interacts with the N terminus of Skp2, interferes with Skp2-p27 interaction, and inhibits ubiquitination of p27. Disruption of p27 function or expression of the Skp2 N terminus prevents Rb from causing G1 arrest. A full-penetrance, inactive Rb mutant fails to interfere with Skp2-p27 interaction but, interestingly, a partial-penetrance Rb mutant that is defective for E2F binding retains full activity in inhibiting Skp2-p27 interaction and can induce G1 cell cycle arrest with wild-type kinetics. These results identify an Rb-Skp2-p27 pathway in Rb function, which may be involved in inhibition of tumor progression.
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U2 - 10.1016/j.molcel.2004.09.029
DO - 10.1016/j.molcel.2004.09.029
M3 - Article
C2 - 15469821
AN - SCOPUS:4944252223
SN - 1097-2765
VL - 16
SP - 47
EP - 58
JO - Molecular Cell
JF - Molecular Cell
IS - 1
ER -