Annotation Extension Relation:causally upstream of

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Definition

• Relations Ontology definition: p is causally upstream of q if and only if p precedes q and p and q are linked in a causal chain

• property_value: usage Process A is causally_upstream of process B if process A occurs first, and process A causes process B to happen. Processes A and B do not overlap.

Child terms

• causally upstream of, positive effect
• causally upstream of, negative effect

Scope of use

Domain

BFO:0000007 ! process (Biological Process or Molecular Function)

Range

GO:0008150 ! GO:Biological Process

GO:0003674 ! GO:Molecular Function

Annotation Extension Usage Examples

1. Specifying the biological process downstream of regulation of protein levels.

Summary of paper, PMID:24553947:

Loss of PINK1 in PINK1-/- knockout mice decreased HIF-1alpha translation, thus resulting in a lower HIF-1alpha level. PINK-/- mice exhibited significantly reduced induction of HIF-1aplha protein, HIF-1alpha transcriptional activity, and hypoxia-responsive gene up regulation

Background, and paper in more detail

HIF-alpha is a transcription factor that under hypoxia binds to hypooxia-response elements (HREs) in the promoter, and up regulates HRE-containing genes that govern a multitude of cellular functions. In PMID 24553947, the inductions of three HRE genes (GLUT-1, BNIP3 and VEGFalpha) were examined. BNIP3 and VEGFalpha mRNA increased more dramatically in PINK+/+ than PINK -/- primary neurons treated with 1%O2. And PINK+/+ MEFs had significantly higher levels of GLUT-1 and BNIP3 mRNA. Luciferase assays demonstrate reduced HIF-1alpha activity in PINK1-/- knockout MEFs

DB (Col 2)	Object (Col 3)	GO ID (Col 5)	Reference (Col 6)	Evidence (Col 7)	Extension (Col 16)
Q99MQ3	Pink1	GO:0045727 positive regulation of translation	PMID:24553947	IMP	causally_upstream_of GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity has_input(UniProtKB:Q61221 Hif1a) HIF1alpha
Q99MQ3	Pink1	GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity	PMID:24553947	IMP	has_input(UniProtKB:Q61221 Hif1a)

Using examples (from above) to demonstrate Folding_and_Unfolding using the relationship causally_upstream_of

1. Specifying the biological process upstream of the regulation of mRNA expression levels.

Summary of paper, PMID:11875061:

Transfection of mouse Foxa2 into rat INS-r3 cells results in blunted glucose-stimulated insulin secretion and drastically decreased mRNA levels of insulin, GLUT2 and glucokinase. In contrast, loss of Foxa2 function leads to up-regulation of hexokinase (HK) I and II and glucokinase (HK-IV) mRNA expression and down-regulation of KATP Channel Subunits Sur1 and Kir6.2 mRNA expression. High levels of the glucose transporter Glut2, enable rapid equilibration of glucose across the plasma membrane, whereas low levels of high affinity hexokinase isoforms (hexokinases I, II, and III) optimize glucose sensing in the physiological blood glucose range. Glucokinase (hexokinase IV) is rate-limiting enzyme for glucose metabolism, and determines the glucose sensing in pancreatic β-cells.

Folded/unfolded	DB (Col 2)	Object (Col 3)	GO ID (Col 5)	Reference (Col 6)	Evidence (Col 7)	Extension (Col 16)
Unfolded	P35583	Foxa2	GO:0000433 negative regulation of transcription from RNA polymerase II promoter by glucose	11875061	IDA	causally_upstream_of GO:2000971 negative regulation of detection of glucose has_input(UniProtKB:P52792 GCK) Glucokinase
Folded	P35583	Foxa2	GO:0000433 negative regulation of transcription from RNA polymerase II promoter by glucose	11875061	IDA	No new GO term created

OWL class expression: GO:0000433 negative regulation of transcription from RNA polymerase II promoter by glucose AND causally_upstream_of SOME GO:2000971 negative regulation of detection of glucose AND has_input SOME UniProtKB:P52792 Glucokinase

Date last reviewed: 2020-12-11

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