Acts upstream of or within, positive effect

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The acts upstream of or within, positive effect annotation relation is used when the mechanism relating the gene product's activity to the Biological Process is not known. However, the observed experimental outcome indicates that, ultimately, the gene product's activity has a positive effect on the process. Annotations using this relation often come from mutant phenotypes for which further characterization has not been performed, but the authors wish to report the effect that the gene has on a process.

Examples of Usage

Example 1: Taxonomically Restricted Genes with Essential Functions Frequently Play Roles in Chromosome Segregation in Caenorhabditis elegans and Saccharomyces cerevisiae


  • This paper examines three aspects of taxonomically restricted gene function: "where and when these genes are expressed, the physical interactions made by the novel encoded proteins, and their in vivo functions."


  • The in vivo function of a subset of essential, taxonomically restricted genes in C. elegans was assessed by RNA interference (RNAi). These experiments demonstrate that loss of function of these genes results in mitotic chromosome-segregation defects in early embryos (Figure 4).


  • Since the mechanism of action of these genes is not yet known, but their overall role appears to be that of a positive effect on mitotic chromosome segregation, the resulting GO annotations are:
 acts usptream of or within, positive effect mitotic sister chromatid segregation (GO:0000070)

GO-CAM Model

Example 2: Caffeine alters glutamate-aspartate transporter function and expression in rat retina.

INTRO & BACKGROUND The role of D-aspartate as a neurotransmitter is not as clearly established as that of L-glutamate, but there is convincing evidence that it exists (see PMID:25868730 and references therein):

  • D-aspartate is present in the brain.
  • D-aspartate acts as a neurotransmitter via binding to the of L-glutamate receptor.
  • A specific transporter responsible for putative vesicular accumulation of D-Asp has never been identified
  • D-aspartate likely gets imported by the l-Glu/l-Asp transporter: while it is stereoselective for l-enantiomer of Glu, it recognizes and transport both l- and d-Asp with the same efficiency

Based on this information, it is not clear how D-aspartate import into cells can be selectively regulated.

RESULTS In PMID:27663541, the authors test the effect of A2AR (adenosine receptors) inhibitors caffeine (non-specific for all adenosine receptors), ZM241385 (A2AR inhibitor) and DPCPX (A1AR inhibitor). The basis of this is that purinergic receptors can regulate EAAT function (citing PMID:23032072 and PMID:25869810)

  • Figure 1B: levels of D-aspartate vary during the development of the rat retina. This is likely mediated by the L-glu transporter: since these are Na-dependent, they tested transport in the absence of sodium ions, which completely abolished D-aspartate uptake.
    • no annotation from this data
  • Fig 2A: DL-TBOA, an inhibitor of all EAAs (glu or excitatory aa transporters): D-aspartate uptake was reduced by the inhibitor, indicating that some of the EAAs transport D-aspartate
    • no annotation from this data, because we don't know which transporter transports D-asp.
  • Fig 4A: caffeine inhibited D-aspartate at some stages of rat retina development (but not all).
    • no annotation from this data
  • Fig 5A: caffeine and ZM241385 (A2AR) inhibited about 40-50% of D-asp uptake.
    • Adora2a (A2AR) acts upstream of or within, positive effect (regulation of??) D-aspartate import across plasma membrane


  Adora2a (A2AR) acts upstream of or within, positive effect (regulation of??) D-aspartate import across plasma membrane

(since we don't know the exact mechanism). (It is also not clear that the authors are really looking at regulation.)

  • One caveat of this study is that they didn't look at L-glutamate import. It is not clear whether D-aspartate import (or even L-glutamate import) is specifically regulated; however Adora2a inhibition does affect D-aspartate import.

GO-CAM Model

Quality Control Checks

Relations Ontology

acts upstream of or within, positive effect

Review Status

Last reviewed: March 9, 2018

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