Hif1a (rat, UniProt O35800) - manual literature synthesis

No deep-research API was available for this review; this file was compiled by hand from
the cached publications in publications/ and the UniProt record
(Hif1a-uniprot.txt). Each statement carries its provenance.

Identity and domain architecture

• Rat Hif1a encodes the 825-residue hypoxia-inducible factor 1-alpha (UniProt O35800,
  RGD:61928, GeneID 29560). The rat cDNA was cloned from primary hepatocytes and shown
  to be functional: PMID:11237857
• Domains (UniProt FT lines): bHLH (17-70), PAS 1 (85-158), PAS 2 (228-298), PAC
  (302-345), oxygen-dependent degradation domain ODD (401-602), N-terminal
  transactivation domain NTAD (530-574), inhibitory domain (575-784) and C-terminal
  transactivation domain CTAD (785-825). Belongs to the bHLH-PAS family
  (PANTHER PTHR23043:SF7, InterPro IPR001321 HIF-1_alpha).

Molecular function

• HIF-1 is an alpha/beta heterodimer. UniProt (by similarity to human Q16665):
  "Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within
  the hypoxia response element (HRE) of target gene promoters".
• Rat brain experiments show heterodimerisation with ARNT1 and the neuronal ARNT2:
  PMID:11029639
• HRE binding and activation of rat target promoters: tyrosine hydroxylase
  PMID:12675925;
  frataxin in H9C2 cardiomyocytes PMID:26071548; enolase-1 in nucleus pulposus cells
  PMID:20496369.
• HIF-1 can also repress through HREs: PMID:20496369.
• DNA-binding activity in rat cells: PMID:18614764;
  supershift of the HRE complex by HIF-1alpha and HIF-1beta antibodies in neuronal
  cultures (PMID:10559391).
• Coactivator recruitment: Ref-1/APE1 and p300 co-immunoprecipitate with HIF-1 on the
  rat pulmonary artery endothelial VEGF HRE PMID:15084519. Recruitment of p300/CBP by the CTAD is blocked by FIH
  asparaginyl hydroxylation PMID:21335549.

Oxygen-dependent regulation (HIF-1alpha as a substrate)

• PMID:21335549 The same study examined HIF-1alpha
  in rat kidney PMID:21335549, showing that
  asparaginyl hydroxylation persists in vivo while the protein accumulates.
• p53-driven ubiquitination and degradation of HIF1A in rat H9c2 cardiac cells is
  reversed by Akt (PMID:19950214). These are regulatory inputs on HIF-1alpha, not
  activities of HIF-1alpha.

Cellular location

• Nuclear in rat cells exposed to hypoxia or other inducers (PMID:18614764,
  PMID:18248612, PMID:22129453). UniProt: "Cytoplasmic in normoxia, nuclear
  translocation in response to hypoxia (By similarity)" and speckle localisation with
  HIF3A (by similarity to mouse).

Biological roles in rat (mostly target-gene consequences)

• Cellular response to hypoxia: siRNA against HIF-1alpha abolishes purine-nucleoside
  protection of hypoxic PC12 cells and neurons (PMID:18248612); HIF-1alpha mediates
  hypoxic activation of the PNMT promoter, largely via Egr-1 and Sp1 (PMID:19220706).
• Angiogenesis/VEGF: knockdown impairs post-ischemic bmEPC homing and sprouting in rat
  brain PMID:30052311; VEGF
  induction in astrocytes is only partly HIF-1alpha-dependent (PMID:18614764).
• Proliferation and apoptosis: HIF-1alpha knockdown suppresses hypoxic PASMC
  proliferation (PMID:16489407); HIF-1 inhibition promotes VSMC apoptosis via hexokinase
  2 (PMID:20498255); pharmacological HIF-1alpha suppression blocks hypoxia-induced
  myocyte apoptosis with Bnip3 (PMID:20224844).
• Many rat studies report only that HIF-1alpha mRNA or protein changes under a stimulus
  (cobalt, CO, cyanide, insulin, IL-1beta, estrogen, stretch, glucose, exercise, noise
  stress, etc.); they establish induction of Hif1a, not a step performed by it.
• One annotated study (PMID:30404558) concludes that suppression of stress granules in
  Hif1a shRNA cells is an RNAi artefact: PMID:30404558

Open questions

• Rat brain HIF-1alpha splice variants and the HIF-1alpha/ARNT2 dimer did not recognise
  the Epo HRE (PMID:11029639); the DNA sites and target genes of this neuronal dimer are
  unknown.