Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression

Abstract

The C-terminal activation domain (C-TAD) of the hypoxiainducible transcription factors HIF-1a and HIF-2a 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 hypoxiaresponsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (DCH1) 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 B35-50% 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 B70%. 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.

A Membrane Protease Regulates Energy Production in Macrophages by Activating Hypoxia-inducible Factor-1 via a Non-proteolytic Mechanism

“…Under oxygen-rich conditions, HIF prolyl hydroxylases (PHDs) mediate hydroxylation of proline residues in the oxygen-dependent degradation domain of HIF-1␣, leading to degradation of the protein in a proteasome-dependent manner (22,23). In addition, FIH-1 mediates hydroxylation of an asparagine residue (Asn 803 ) located in the CAD of HIF-1␣ in an oxygen-dependent manner (24,25) and prevents HIF-1␣ from binding the transcriptional co-activator p300/ CBP (26). Mint3 inhibits FIH-1 activity by competing with HIF-1␣ for binding to FIH-1 (19).…”

Hypoxia induces a novel signature of chromatin modifications and global repression of transcription

“…It is known that hypoxia-inducible factor 1 (HIF-1) drives much of hypoxic gene activation and interacts with histone acetyltransferases p300, CBP and SRC-1 [4]. Although the interaction between HIF-1 and CBP/p300 is critical for the activation of a large percentage of hypoxia-inducible genes [5], there are few determinations of histone acetylation levels at the promoters of hypoxia-responsive genes [6]. Additionally, the variety of histone modifications investigated globally and at the promoters of hypoxia-responsive genes is even more limited.…”

Hypoxic microenvironment and hepatocellular carcinoma treatment

“…The complicated and sophisticated pathways underlying hypoxia have been extensively investigated, and HIFs are identified to play pivotal roles under hypoxia, which has attracted most attention in this field for the last decades [6,8] . Yet recently, the findings on the HIFs-independent regulation of tumor angiogenesis and chemoresistance under hypoxic conditions have challenged this notion and raised the possibility that the other important signaling pathways may also participate and promote the progression and malignance of HCC [10][11][12][13][14] .…”

“…Abnormal microvasculature and unrestrained proliferation of HCC cells lead to oxygen deficiency [6,7] . Hypoxia is involved in multiple biological process of HCC and promotes tumor aggressiveness, chemoresistance and immunotherapy resistance [8,9] . Consequently, the hypoxic microenvironment has been regarded as promising target for HCC treatments.…”

“…Under hypoxia, hypoxia-induced factors (HIFs) would be stabilized to trigger the transactivation of a series of hypoxia-response genes which promote the malignance of HCC. Thus, the transcription factors HIFs have been regarded as master regulators of hypoxic microenvironment [8] . In contrast, several lines of evidence also implicated the HIF-independent hypoxia responses [10][11][12][13][14] .…”