Dissociation of Bone Morphogenetic Protein-Mediated Growth Arrest and Apoptosis of Mouse B Cells by HPV-16 E6/E7

We have previously found that bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-β family, induces cell-cycle arrest in the G1 phase and apoptotic cell death of HS-72 mouse hybridoma cells. In this study, we show that BMP-2 did not alter expression of cyclin D, cyclin E...

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Bibliographic Details
Published in:Experimental cell research 2000-05, Vol.257 (1), p.198-205
Main Authors: Yamato, Kenji, Hashimoto, Shinichi, Okahashi, Nobuo, Ishisaki, Akira, Nonaka, Koji, Koseki, Takeyoshi, Kizaki, Masahiro, Ikeda, Yasuo, Nishihara, Tatsuji
Format: Article
Language:English
Subjects:
Animals
apoptosis
Apoptosis - physiology
B-Lymphocytes - pathology
B-Lymphocytes - physiology
BMP
Bone Morphogenetic Protein 2
Bone Morphogenetic Proteins - physiology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - physiology
E6/E7
G1 arrest
G1 Phase - physiology
HPV-16 E7
Humans
Hybridomas
Mice
Oncogene Proteins, Viral - physiology
p21CIP1/WAF1
Papillomavirus E7 Proteins
Repressor Proteins
Signal Transduction - physiology
Transforming Growth Factor beta
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Summary:We have previously found that bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-β family, induces cell-cycle arrest in the G1 phase and apoptotic cell death of HS-72 mouse hybridoma cells. In this study, we show that BMP-2 did not alter expression of cyclin D, cyclin E, cyclin-dependent kinase 2 (CDK2), CDK4, p27KIP1, p16INK4a, or p15INK4b, but enhanced expression of p21CIP1/WAF1. Accumulation of p21CIP1/WAF1 resulted in increased binding of p21CIP1/WAF1 to CDK4 and concomitantly caused a profound decrease in the in vitro retinoblastoma protein (Rb) kinase activity of CDK4. Furthermore, the ectopic expression of human papilloma virus type-16 E7, an inhibitor of p21CIP1/WAF1 and Rb, reverted G1 arrest induced by BMP-2. Expression of E6/E7, without increasing the p53 level, blocked inhibition of Rb phosphorylation and G1 arrest, but did not attenuate cell death in BMP-treated HS-72 cells. Taken together, these results suggest that inhibition of Rb phosphorylation by p21CIP1/WAF1 is responsible for BMP-2-mediated G1 arrest and that BMP-2-induction of apoptosis might be independent of Rb hypophosphorylation.
ISSN:0014-4827
1090-2422
DOI:10.1006/excr.2000.4876