Two Transactivation Mechanisms Cooperate for the Bulk of HIF-1-responsive Gene Expression

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2005 Oct 21

PMID 16237459

Citations 91

Authors

Lawryn H Kasper

Faycal Boussouar

Kelli Boyd

Wu Xu

Michelle Biesen

Jerold Rehg

Troy A Baudino

John L Cleveland

Paul K Brindle

Affiliations

Soon will be listed here.

Abstract

The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha binds the CH1 domains of the related transcriptional coactivators CREB-binding protein (CBP) and p300, an oxygen-regulated interaction thought to be highly essential for hypoxia-responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (DeltaCH1) of CBP and p300 that abrogate their interactions with the C-TAD, revealing that the CH1 domains of CBP and p300 are genetically non-redundant and indispensable for C-TAD transactivation function. Surprisingly, the CH1 domain was only required for an average of approximately 35-50% of global HIF-1-responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSA(S)) accounts for approximately 70%. Both pathways are required for greater than 90% of the response for some target genes. Our findings suggest that a novel functional interaction between the protein acetylases CBP and p300, and deacetylases, is essential for nearly all HIF-responsive transcription.

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References

Giaccia A, Siim B, Johnson R . HIF-1 as a target for drug development. Nat Rev Drug Discov. 2003; 2(10):803-11. DOI: 10.1038/nrd1199. View

Wood M, Kaplan M, Park A, Blanchard E, Oliveira A, Lombardi T . Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn Mem. 2005; 12(2):111-9. PMC: 1074328. DOI: 10.1101/lm.86605. View

Bruick R . Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev. 2003; 17(21):2614-23. DOI: 10.1101/gad.1145503. View

Wu Y, Zhang X, Zehner Z . c-Jun and the dominant-negative mutant, TAM67, induce vimentin gene expression by interacting with the activator Sp1. Oncogene. 2003; 22(55):8891-901. DOI: 10.1038/sj.onc.1206898. View

Kang-Decker N, Tong C, Boussouar F, Baker D, Xu W, Leontovich A . Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency. Cancer Cell. 2004; 5(2):177-89. DOI: 10.1016/s1535-6108(04)00022-4. View

Simone C, Stiegler P, Forcales S, Bagella L, De Luca A, Sartorelli V . Deacetylase recruitment by the C/H3 domain of the acetyltransferase p300. Oncogene. 2004; 23(12):2177-87. DOI: 10.1038/sj.onc.1207327. View

Poellinger L, Johnson R . HIF-1 and hypoxic response: the plot thickens. Curr Opin Genet Dev. 2004; 14(1):81-5. DOI: 10.1016/j.gde.2003.12.006. View

Zhou X, Shibusawa N, Naik K, Porras D, Temple K, Ou H . Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nat Med. 2004; 10(6):633-7. DOI: 10.1038/nm1050. View

Alarcon J, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel E . Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 2004; 42(6):947-59. DOI: 10.1016/j.neuron.2004.05.021. View

10.

Korzus E, Rosenfeld M, Mayford M . CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron. 2004; 42(6):961-72. PMC: 8048715. DOI: 10.1016/j.neuron.2004.06.002. View

11.

Kung A, Zabludoff S, France D, Freedman S, Tanner E, Vieira A . Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell. 2004; 6(1):33-43. DOI: 10.1016/j.ccr.2004.06.009. View

12.

Matt T, Martinez-Yamout M, Dyson H, Wright P . The CBP/p300 TAZ1 domain in its native state is not a binding partner of MDM2. Biochem J. 2004; 381(Pt 3):685-91. PMC: 1133877. DOI: 10.1042/BJ20040564. View

13.

Kalkhoven E . CBP and p300: HATs for different occasions. Biochem Pharmacol. 2004; 68(6):1145-55. DOI: 10.1016/j.bcp.2004.03.045. View

14.

Giaccia A, Simon M, Johnson R . The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease. Genes Dev. 2004; 18(18):2183-94. PMC: 517513. DOI: 10.1101/gad.1243304. View

15.

Kato H, Tamamizu-Kato S, Shibasaki F . Histone deacetylase 7 associates with hypoxia-inducible factor 1alpha and increases transcriptional activity. J Biol Chem. 2004; 279(40):41966-74. DOI: 10.1074/jbc.M406320200. View

16.

Messina D, Glasscock J, Gish W, Lovett M . An ORFeome-based analysis of human transcription factor genes and the construction of a microarray to interrogate their expression. Genome Res. 2004; 14(10B):2041-7. PMC: 528918. DOI: 10.1101/gr.2584104. View

17.

Herschlag D, Johnson F . Synergism in transcriptional activation: a kinetic view. Genes Dev. 1993; 7(2):173-9. DOI: 10.1101/gad.7.2.173. View

18.

Ferrara N, Chen H, Dowd M, Lu L, OShea K, Hillan K . Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996; 380(6573):439-42. DOI: 10.1038/380439a0. View

19.

Kobayashi A, Sogawa K, Fujii-Kuriyama Y . CBP/p300 functions as a possible transcriptional coactivator of Ah receptor nuclear translocator (Arnt). J Biochem. 1997; 122(4):703-10. DOI: 10.1093/oxfordjournals.jbchem.a021812. View

20.

Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K . Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J. 1999; 18(7):1905-14. PMC: 1171276. DOI: 10.1093/emboj/18.7.1905. View