p27Kip1 overexpression causes apoptotic death of mammalian cells.
p27KiP1, a member of the Cip/Kip family of cyclin-dependent kinase (cdk) inhibitors, has been implicated in mediating G1 arrest in response to a variety of growth inhibitory signals. Its importance in regulating cell growth is emphasized by the fact that mice lacking p27Kip1 are abnormally large and display hyperplasia of multiple tissues. However, these mice retain the ability to undergo G1 arrest in response to growth inhibitory signals, suggesting that p27KiP1 may serve other functions important for controlling tissue growth. In the present study, we utilized an adenoviral vector-based expression system to examine the consequences of p27Kip1 overexpression in the human carcinoma cell lines A549, HeLa and RKO, in human melanoma SK-MEL-110 cells, in human lung fibroblasts IMR90 and in the rat fibroblast line Rat1. We demonstrate that overexpression of p27Kip1 leads to apoptotic cell death in all cell types, and further show that ectopic expression of Bcl-2 can protect HeLa cells from apoptosis mediated by p27Kip1 overexpression. To our knowledge, this is the first study demonstrating that p27Kip1 can induce apoptosis. Our findings provide new insight into the possible functions of this growth regulatory protein, and support the potential utility of gene therapeutic approaches aimed at elevating p27Kip1 expression for treatment of human cancers.
Wang
X
X
Laboratory of Biological Chemistry, National Institute on Aging, Baltimore, Maryland 21224, USA.
Gorospe
M
M
Huang
Y
Y
Holbrook
N J
NJ
D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005822:Genetic Vectors / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008545:Melanoma; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27