Disease relevance of sima

• We also report a null mutation in dHIF-alpha/sima, which is unable to adapt to hypoxia but is fully viable in normoxic conditions [1].

High impact information on sima

• The alpha subunit of HIF is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF [2].
• Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension [3].
• We show that the bHLH-PAS proteins Similar (Sima) and Tango (Tgo) function as HIF-alpha and HIF-beta homologues, respectively, and demonstrate a conserved mode of regulation for Sima by oxygen [4].
• In mammalian systems, the heterodimeric basic helix-loop-helix (bHLH)-PAS transcription hypoxia-inducible factor (HIF) has emerged as the key regulator of responses to hypoxia [4].
• Tight conservation of the HIF/prolyl hydroxylase system in Drosophila provides a new focus for understanding oxygen homeostasis in intact multicellular organisms [4].

Chemical compound and disease context of sima

• HIF-dependent changes in candidate target gene expression were detected through variously effective stimuli: hypoxia (strong) > iron chelation, e.g. desferrioxamine (moderate) >> transition metals, e.g. cobalt approximately normoxia (ineffective) [5].

Biological context of sima

• These results indicate that the main functions of Fatiga in development, including control of cell size, involve the regulation of dHIF/Sima [1].
• Although hypoxia-inducible factor-alpha (HIFalpha) subunit-specific hydroxylation and proteolytic breakdown explain the binary switch between the presence (hypoxia) and absence (normoxia) of HIFs, little is known of the mechanisms that fine-tune HIF activity under constant, rather than changing, oxygen tensions [5].
• This complex (HIF-D) resembled mammalian hypoxia inducible factor (HIF-1) in DNA sequence specificity, abrogation of induction by cycloheximide, induction by desferrioxamine and redox sensitivity of DNA binding [6].

Associations of sima with chemical compounds

• The hypoxic response is mediated by hypoxia-inducible factor (HIF), an alphabeta heterodimeric transcription factor in which both the HIF subunits are members of the basic helix-loop-helix PAS (PER-ARNT-SIM) domain family [7].

Regulatory relationships of sima

• The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-alpha/Sima [8].

Other interactions of sima

• Strikingly, loss-of-function mutations of sima rescued the developmental defects observed in fatiga mutants and enabled survival to adulthood [1].

References