Annotation Extension Relation:causally upstream of

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Definition

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

• None

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 upstream of the regulation of protein levels.

Summary of paper:

Transfection of RGC-32 and SMAD3 leads to an increase in the protein expression of extracellular matrix protein fibronectin. RGC-32 mediates transforming growth factor-β1-induced epithelial-mesenchymal transition (EMT) a process associated with the massive deposition of matrix and the synthesis of a fibrosis matrix.

DB (Col 2)	Object (Col 3)	GO ID (Col 5)	Reference (Col 6)	Evidence (Col 7)	Extension (Col 16)
P84022	SMAD3	GO:0010468 regulation of gene expression	PMID:21307346	IDA	causally_upstream_of GO:1901201 regulation of extracellular matrix assembly has_regulation_target(UniProtKB:P02751 FN1) Fibronectin
P84022	SMAD3	GO:1901201 regulation of extracellular matrix assembly	PMID:21307346	IDA
Q9H4X1	RGCC (RGC-32)	GO:0010468 regulation of gene expression	PMID:21307346	IDA	causally_upstream_of GO:1901201 regulation of extracellular matrix assembly has_regulation_target(UniProtKB:P02751 FN1) Fibronectin
Q9H4X1	RGCC (RGC-32)	GO:1901201 regulation of extracellular matrix assembly	PMID:21307346	IDA

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

Summary of paper:

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.

DB (Col 2)	Object (Col 3)	GO ID (Col 5)	Reference (Col 6)	Evidence (Col 7)	Extension (Col 16)
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_regulation_target(UniProtKB:P52792 GCK) Glucokinase
P35583	Foxa2	GO:2000971 negative regulation of detection of glucose	11875061	IDA

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 protein levels.

Summary of paper:

Transfection of RGC-32 and SMAD3 leads to an increase in the protein expression of extracellular matrix protein fibronectin. RGC-32 mediates transforming growth factor-β1-induced epithelial-mesenchymal transition (EMT) a process associated with the massive deposition of matrix and the synthesis of a fibrosis matrix.

Folded/unfolded	DB (Col 2)	Object (Col 3)	GO ID (Col 5)	Reference (Col 6)	Evidence (Col 7)	Extension (Col 16)	Parent terms of new folded GO term
Unfolded	P84022	SMAD3	GO:0010468 regulation of gene expression	PMID:21307346	IDA	causally_upstream_of GO:1901201 regulation of extracellular matrix assembly has_regulation_target(UniProtKB:P02751 FN1) Fibronectin
Folded	P84022	SMAD3	GO:0010468 regulation of gene expression	PMID:21307346	IDA		No new GO term created

OWL class expression:

regulation of gene expression AND causally_upstream_of SOME regulation of extracellular matrix assembly AND has_regulation_target SOME Fibronectin

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

Summary of paper:

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_regulation_target(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:

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