Activation of the cyclin D1 Gene by the E1A-associated Protein p300 through AP-1 Inhibits Cellular Apoptosis

• Published in: The Journal of biological chemistry Vol. 274; no. 48; pp. 34186 - 34195
• Main Authors: Albanese, C, D'Amico, M, Reutens, A T, Fu, M, Watanabe, G, Lee, R J, Kitsis, R N, Henglein, B, Avantaggiati, M, Somasundaram, K, Thimmapaya, B, Pestell, R G
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 26.11.1999
• Subjects: Adenovirus E1A Proteins - chemistry; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - physiology; Animals; Apoptosis - genetics; Apoptosis - radiation effects; Binding Sites - genetics; Binding Sites - physiology; Cell Line; COS Cells; CREB-Binding Protein; Cyclin D1 - genetics; Cyclin D1 - metabolism; DNA - genetics; DNA - metabolism; E1A-Associated p300 Protein; Gene Expression Regulation; Humans; Luciferases - genetics; Luciferases - metabolism; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - physiology; p300 protein; Promoter Regions, Genetic - genetics; Protein Binding; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; retinoblastoma protein; Sequence Deletion; Trans-Activators - genetics; Trans-Activators - physiology; Transcription Factor AP-1 - metabolism; Tumor Cells, Cultured; Ultraviolet Rays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.48.34186

The adenovirus E1A protein interferes with regulators of apoptosis and growth by physically interacting with cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein and the coactivator proteins p300/CBP (where CBP is the CREB-binding protein). The p300/CBP proteins occupy a pivotal role in regulating mitogenic signaling and apoptosis. The mechanisms by which cell cycle control genes are directly regulated by p300 remain to be determined. The cyclin D1 gene, which is overexpressed in many different tumor types, encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates PRB. In the present study E1A12S inhibited the cyclin D1 promoter via the amino-terminal p300/CBP binding domain in human choriocarcinoma JEG-3 cells. p300 induced cyclin D1 protein abundance, and p300, but not CBP, induced the cyclin D1 promoter. cyclin D1 or p300 overexpression inhibited apoptosis in JEG-3 cells. The CH3 region of p300, which was required for induction of cyclin D1, was also required for the inhibition of apoptosis. p300 activated the cyclin D1 promoter through an activator protein-1 (AP-1) site at −954 and was identified within a DNA-bound complex with c-Jun at the AP-1 site. Apoptosis rates of embryonic fibroblasts derived from mice homozygously deleted of the cyclin D1 gene ( cyclin D1 − / − ) were increased compared with wild type control on several distinct matrices. p300 inhibited apoptosis in cyclin D1 +/+ fibroblasts but increased apoptosis in cyclin D1 − / − cells. The anti-apoptotic function of cyclin D1, demonstrated by sub-G 1 analysis and annexin V staining, may contribute to its cellular transforming and cooperative oncogenic properties.