Skp2B attenuates p53 function by inhibiting prohibitin.
The F-box protein Skp2 and its isoform Skp2B are both overexpressed in breast cancers. Skp2 alters the activity of p53 by inhibiting its interaction with p300 and by promoting p300 degradation. Here, we report that Skp2B also attenuates the activity of p53; however, this effect is independent of p300, suggesting that another mechanism might be involved. Prohibitin, a protein reported to activate p53, was isolated in a two-hybrid screen with the carboxy-terminal domain unique to Skp2B. We observed that prohibitin is a new substrate of Skp2B and that the degradation of prohibitin is responsible for the attenuated activity of p53 in cells overexpressing Skp2B. Furthermore, we show that the activity of p53 is reduced in the mammary glands of Skp2B transgenic mice. This study indicates that both Skp2 and Skp2B attenuate p53 activity through different pathways, suggesting that amplification of the Skp2 locus represents a powerful mechanism to attenuate p53 function in cancer.
Division of Hematology and Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Harish
H
Chander
Max
M
Halpern
Lois
L
Resnick-Silverman
James J
JJ
Manfredi
Doris
D
Germain
D000818:Animals; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D000091402:Prohibitins; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D000091402:Prohibitins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D044786:S-Phase Kinase-Associated Proteins; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse