Destabilization of TIP60 by human papillomavirus E6 results in attenuation of TIP60-dependent transcriptional regulation and apoptotic pathway.
The TIP60 tumor suppressor is a histone acetyltransferase involved in transcriptional regulation, checkpoint activation, and p53-directed proapoptotic pathways. We report that human papillomavirus (HPV) E6 destabilizes TIP60 both in vivo and in vitro. TIP60 binds to the HPV major early promoter and acetylates histone H4 to recruit Brd4, a cellular repressor of HPV E6 expression. Both low- and high-risk HPV E6 destabilize TIP60, thereby derepressing their own promoter. Destabilization of TIP60 by HPV E6 also relieves cellular promoters from TIP60-initiated repression and abrogates p53-dependent activation of apoptotic pathway. Degradation of TIP60, therefore, allows low- and high-risk HPV to promote cell proliferation and cell survival.
Jha
Sudhakar
S
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Vande Pol
Scott
S
Banerjee
Nilam Sanjib
NS
Dutta
Arun Brendan
AB
Chow
Louise T
LT
Dutta
Anindya
A
D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D054731:PDZ Domains; D030361:Papillomavirus Infections / Q000378:metabolism; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D000074443:Lysine Acetyltransferase 5; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; C098489:KAT5 protein, human; C471639:UBE3A protein, human