IGF1 insulin like growth factor 1 [Homo sapiens (human)] - Gene

Summary

Official Symbol: IGF1provided by HGNC
Official Full Name: insulin like growth factor 1provided by HGNC
Primary source: HGNC:HGNC:5464
See related: Ensembl:ENSG00000017427 MIM:147440; AllianceGenome:HGNC:5464
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: IGF; MGF; IGFI; IGF-I
Summary: The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Sep 2015]
Expression: Broad expression in endometrium (RPKM 7.0), fat (RPKM 6.3) and 18 other tissues See more
Orthologs: mouse all
NEW: Try the new Gene table
Try the new Transcript table

Genomic context

Location:: 12q23.2

Exon count:: 7

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	12	NC_000012.12 (102395874..102481839, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	12	NC_060936.1 (102357015..102443074, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	12	NC_000012.11 (102789652..102875525, complement)

Chromosome 12 - NC_000012.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

Go to the top of the page Help

Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

Go to the top of the page Help

See details

Project title: Tissue-specific circular RNA induction during human fetal development
Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
BioProject: PRJNA270632
Publication: PMID 26076956
Analysis date: Mon Apr 2 22:54:59 2018

Bibliography

Go to the top of the page Help

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Characterisation of IGF-1 (rs7136446) and IL-6 (rs1800795) polymorphisms among breast cancer patients in western Algeria.
Title: Characterisation of IGF-1 (rs7136446) and IL-6 (rs1800795) polymorphisms among breast cancer patients in western Algeria.
GH and IGF-1 in skin interstitial fluid and blood are associated with heat loss responses in exercising young adults.
Title: GH and IGF-1 in skin interstitial fluid and blood are associated with heat loss responses in exercising young adults.
Analysis of VEGF, IGF1/2 and the Long Noncoding RNA (lncRNA) H19 Expression in Polish Women with Endometriosis.
Title: Analysis of VEGF, IGF1/2 and the Long Noncoding RNA (lncRNA) H19 Expression in Polish Women with Endometriosis.
When IGF-1 Meets Metabolic Inflammation and Polycystic Ovary Syndrome.
Title: When IGF-1 Meets Metabolic Inflammation and Polycystic Ovary Syndrome.
Short communication: TNF-alpha and IGF-1 regulates epigenetic mechanisms of HDAC2 and HDAC10.
Title: Short communication: TNF-α and IGF-1 regulates epigenetic mechanisms of HDAC2 and HDAC10.
IGF1 promotes human myotube differentiation toward a mature metabolic and contractile phenotype.
Title: IGF1 promotes human myotube differentiation toward a mature metabolic and contractile phenotype.
The role and mechanism of action of miR-483-3p in mediating the effects of IGF-1 on human renal tubular epithelial cells induced by high glucose.
Title: The role and mechanism of action of miR-483-3p in mediating the effects of IGF-1 on human renal tubular epithelial cells induced by high glucose.
Detection rate of IGF-1 variants and their implication to protein binding: study of over 240,000 patients.
Title: Detection rate of IGF-1 variants and their implication to protein binding: study of over 240,000 patients.
Compression Promotes the Osteogenic Differentiation of Human Periodontal Ligament Stem Cells by Regulating METTL14-mediated IGF1.
Title: Compression Promotes the Osteogenic Differentiation of Human Periodontal Ligament Stem Cells by Regulating METTL14-mediated IGF1.
CircUTRN24/miR-483-3p/IGF-1 Regulates Autophagy Mediated Liver Fibrosis in Biliary Atresia.
Title: CircUTRN24/miR-483-3p/IGF-1 Regulates Autophagy Mediated Liver Fibrosis in Biliary Atresia.

Submit: New GeneRIF Correction See all GeneRIFs (1856)

Phenotypes

Go to the top of the page Help

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Growth delay due to insulin-like growth factor type 1 deficiency MedGen: C1837475 OMIM: 608747 GeneReviews: Not available	Compare labs

EBI GWAS Catalog

Description
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk. EBI GWAS Catalog EBI GWAS CatalogPubMed
Identification of 15 loci influencing height in a Korean population. EBI GWAS Catalog EBI GWAS CatalogPubMed
Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

Go to the top of the page Help

See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

Go to the top of the page Help

Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	Insulin-like growth factor-I (IGF-I) and erythropoietin treatment protect against HIV/gp120-mediated neuronal damage in culture and in vivo, in part, through cooperative activation of phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling	PubMed
	env	The fusion of insulin-like growth factor I (IGF I) with stromal cell-derived factor I or alpha1 proteinase inhibitor has the capacity to compete with the binding of HIV-1 gp120 to CD4 receptor	PubMed
Tat	tat	HIV-1 Tat upregulates several anti-apoptotic genes, including AKT-1, AKT-2, BCL2, BCL-XL, and insulin-like growth factor I in vincristine-treated Kaposi's sarcoma cells	PubMed
	tat	Insulin-like growth factor 1 (IGF-1) inhibits HIV-1 Tat-mediated transactivation of the HIV-1 LTR promoter	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

Go to the top of the page Help

Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

Go to the top of the page Help

Markers

RH77802 (e-PCR)
- UniSTS:17665

D12S1962 (e-PCR)
- UniSTS:18699

IGF1 (e-PCR), detects polymorphism
- UniSTS:49688

D12S2023 (e-PCR)
- UniSTS:7967

G10727 (e-PCR)
- UniSTS:31781

D12S1103 (e-PCR)
- UniSTS:52274

WI-21639 (e-PCR)
- UniSTS:7237

D12S1074 (e-PCR)
- UniSTS:42570

NoName (e-PCR)
- UniSTS:482382

A009K41 (e-PCR)
- UniSTS:40791

WI-18971 (e-PCR)
- UniSTS:71779

Igf1 (e-PCR), detects polymorphism
- UniSTS:143467

IGF1_1346 (e-PCR)
- UniSTS:277356

GDB:181478 (e-PCR)
- UniSTS:155246

RH18058 (e-PCR)
- UniSTS:3990

GDB:384821 (e-PCR)
- UniSTS:157100

Igf1 (e-PCR), detects polymorphism
- UniSTS:516546

G32627 (e-PCR)
- UniSTS:117210

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables growth factor activity	IDA Inferred from Direct Assay more info	PubMed
enables hormone activity	IBA Inferred from Biological aspect of Ancestor more info
enables hormone activity	IDA Inferred from Direct Assay more info	PubMed
enables insulin receptor binding	IPI Inferred from Physical Interaction more info	PubMed
enables insulin-like growth factor receptor binding	IBA Inferred from Biological aspect of Ancestor more info
enables insulin-like growth factor receptor binding	IDA Inferred from Direct Assay more info	PubMed
enables insulin-like growth factor receptor binding	IMP Inferred from Mutant Phenotype more info	PubMed
enables insulin-like growth factor receptor binding	IPI Inferred from Physical Interaction more info	PubMed
enables integrin binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in Ras protein signal transduction	TAS Traceable Author Statement more info	PubMed
involved_in activation of protein kinase B activity	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in bone mineralization involved in bone maturation	IDA Inferred from Direct Assay more info	PubMed
acts_upstream_of_or_within cell activation	IDA Inferred from Direct Assay more info	PubMed
involved_in cell population proliferation	IBA Inferred from Biological aspect of Ancestor more info
involved_in cell population proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cell surface receptor signaling pathway via STAT	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to amyloid-beta	IGI Inferred from Genetic Interaction more info	PubMed
involved_in epithelial to mesenchymal transition	NAS Non-traceable Author Statement more info	PubMed
involved_in glycolate metabolic process	TAS Traceable Author Statement more info	PubMed
involved_in insulin-like growth factor receptor signaling pathway	IBA Inferred from Biological aspect of Ancestor more info
involved_in insulin-like growth factor receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in insulin-like growth factor receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in muscle hypertrophy	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in muscle organ development	TAS Traceable Author Statement more info	PubMed
involved_in myoblast differentiation	IDA Inferred from Direct Assay more info	PubMed
involved_in myoblast proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in myotube cell development	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of amyloid-beta formation	IGI Inferred from Genetic Interaction more info	PubMed
involved_in negative regulation of apoptotic process	IBA Inferred from Biological aspect of Ancestor more info
involved_in negative regulation of apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of extrinsic apoptotic signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of gene expression	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of interleukin-1 beta production	IGI Inferred from Genetic Interaction more info	PubMed
involved_in negative regulation of neuroinflammatory response	IGI Inferred from Genetic Interaction more info	PubMed
involved_in negative regulation of oocyte development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of release of cytochrome c from mitochondria	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of smooth muscle cell apoptotic process	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of tumor necrosis factor production	IGI Inferred from Genetic Interaction more info	PubMed
involved_in negative regulation of vascular associated smooth muscle cell apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of D-glucose import	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of DNA binding	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of DNA-templated transcription	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of ERK1 and ERK2 cascade	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of MAPK cascade	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of Ras protein signal transduction	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of activated T cell proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of calcineurin-NFAT signaling cascade	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of cardiac muscle hypertrophy	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of cardiac muscle hypertrophy	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of cell growth involved in cardiac muscle cell development	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of cell growth involved in cardiac muscle cell development	IGI Inferred from Genetic Interaction more info	PubMed
involved_in positive regulation of cell migration	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of cell population proliferation	IBA Inferred from Biological aspect of Ancestor more info
involved_in positive regulation of cell population proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of cell population proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of epithelial cell proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of fibroblast proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of gene expression	IGI Inferred from Genetic Interaction more info	PubMed
involved_in positive regulation of glycogen biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of glycolytic process	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of glycoprotein biosynthetic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of insulin-like growth factor receptor signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of mitotic nuclear division	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of osteoblast differentiation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of peptidyl-tyrosine phosphorylation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IBA Inferred from Biological aspect of Ancestor more info
involved_in positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	NAS Non-traceable Author Statement more info	PubMed
involved_in positive regulation of protein secretion	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of smooth muscle cell migration	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of smooth muscle cell proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription regulatory region DNA binding	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of trophectodermal cell proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of vascular associated smooth muscle cell proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in protein stabilization	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in proteoglycan biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
involved_in proteoglycan biosynthetic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to heat	IDA Inferred from Direct Assay more info	PubMed
involved_in signal transduction	TAS Traceable Author Statement more info	PubMed
involved_in skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration	IDA Inferred from Direct Assay more info	PubMed
involved_in skeletal system development	TAS Traceable Author Statement more info	PubMed
involved_in wound healing	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
part_of alphav-beta3 integrin-IGF-1-IGF1R complex	IDA Inferred from Direct Assay more info	PubMed
located_in exocytic vesicle	ISS Inferred from Sequence or Structural Similarity more info
located_in extracellular region	NAS Non-traceable Author Statement more info	PubMed
located_in extracellular region	TAS Traceable Author Statement more info
is_active_in extracellular space	IBA Inferred from Biological aspect of Ancestor more info
located_in extracellular space	IDA Inferred from Direct Assay more info	PubMed
part_of insulin-like growth factor binding protein complex	IC Inferred by Curator more info	PubMed
part_of insulin-like growth factor ternary complex	IDA Inferred from Direct Assay more info	PubMed
located_in platelet alpha granule lumen	TAS Traceable Author Statement more info

General protein information

Go to the top of the page Help

Preferred Names: insulin-like growth factor 1; insulin-like growth factor I

Names: insulin-like growth factor 1 (somatomedin C); insulin-like growth factor IB; mechano growth factor; somatomedin-C

NCBI Reference Sequences (RefSeq)

Go to the top of the page Help

NEW Try the new Transcript table

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_011713.1 RefSeqGene

Range

5038..89727

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_000618.5 → NP_000609.1 insulin-like growth factor 1 isoform 4 preproprotein

See identical proteins and their annotated locations for NP_000609.1

Status: REVIEWED

Description

Transcript Variant: This variant (4) lacks an alternate frame-shifting exon in the 3' coding region, compared to variant 1, resulting in a protein (isoform 4) with a novel C-terminus, compared to isoform 1. This isoform is also known as IA. Variants 4 and 7 both encode the same isoform (4).

Source sequence(s)

AB209184, AC010202

Consensus CDS

CCDS9091.1

UniProtKB/TrEMBL

Q59GC5, Q5U743

Related

ENSP00000337612.7, ENST00000337514.11

Conserved Domains (1) summary

cd04368
Location:49 → 116

IlGF; insulin_like growth factors; specific to vertebrates. Members include a number of peptides including insulin-like growth factors I and II, which play a variety of roles in controlling processes such as growth, differentiation, and reproduction. On a ...
NM_001111283.3 → NP_001104753.1 insulin-like growth factor 1 isoform 1 preproprotein

See identical proteins and their annotated locations for NP_001104753.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1). This isoform is also known as IC.

Source sequence(s)

AC010202, AL603526, U40870

Consensus CDS

CCDS44961.1

UniProtKB/TrEMBL

Q13429

Related

ENSP00000376638.3, ENST00000392905.7

Conserved Domains (1) summary

cd04368
Location:49 → 116

IlGF; insulin_like growth factors; specific to vertebrates. Members include a number of peptides including insulin-like growth factors I and II, which play a variety of roles in controlling processes such as growth, differentiation, and reproduction. On a ...
NM_001111284.2 → NP_001104754.1 insulin-like growth factor 1 isoform 2 precursor

See identical proteins and their annotated locations for NP_001104754.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) differs in the 5' UTR and has multiple coding region differences, compared to variant 1. These differences cause translation initiation from a distinct start codon and result in an isoform (2) with novel N- and C-termini, compared to isoform 1. This isoform is also known as IIA. This isoform (2) may undergo proteolytic processing similar to isoform 1.

Source sequence(s)

AC010202, M37484

Consensus CDS

CCDS44960.1

UniProtKB/TrEMBL

Q13429

Related

ENSP00000416811.2, ENST00000424202.6

Conserved Domains (1) summary

cd04368
Location:33 → 100

IlGF; insulin_like growth factors; specific to vertebrates. Members include a number of peptides including insulin-like growth factors I and II, which play a variety of roles in controlling processes such as growth, differentiation, and reproduction. On a ...
NM_001111285.3 → NP_001104755.1 insulin-like growth factor 1 isoform 3 preproprotein

See identical proteins and their annotated locations for NP_001104755.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) differs in the 3' coding region and 3' UTR, compared to variant 1, resulting in a protein (isoform 3) with a novel C-terminus, compared to isoform 1. This isoform is also known as IB. Variants 3 and 5 both encode the same isoform (3).

Source sequence(s)

AC010202, CA445905, X56774

UniProtKB/Swiss-Prot

B2RWM7, E9PD02, P01343, P05019, Q14620

Related

ENSP00000302665.8, ENST00000307046.8

Conserved Domains (1) summary

cd04368
Location:49 → 116

IlGF; IlGF, insulin_like growth factors; specific to vertebrates. Members include a number of peptides including insulin-like growth factors I and II, which play a variety of roles in controlling processes such as growth, differentiation, and reproduction. On ...
NM_001414005.1 → NP_001400934.1 insulin-like growth factor 1 isoform 3 preproprotein

Status: REVIEWED

Source sequence(s)

AC010202

UniProtKB/Swiss-Prot

B2RWM7, E9PD02, P01343, P05019, Q14620
NM_001414006.1 → NP_001400935.1 insulin-like growth factor 1 isoform 5 precursor

Status: REVIEWED

Source sequence(s)

AC010202
NM_001414007.1 → NP_001400936.1 insulin-like growth factor 1 isoform 4 preproprotein

Status: REVIEWED

Source sequence(s)

AC010202

UniProtKB/TrEMBL

Q59GC5, Q5U743

Related

ENSP00000494228.1, ENST00000644491.1

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000012.12 Reference GRCh38.p14 Primary Assembly

Range

102395874..102481839 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_017019263.3 → XP_016874752.1 insulin-like growth factor I isoform X3

Conserved Domains (1) summary

cd04368
Location:66 → 133

IlGF; IlGF, insulin_like growth factors; specific to vertebrates. Members include a number of peptides including insulin-like growth factors I and II, which play a variety of roles in controlling processes such as growth, differentiation, and reproduction. On ...
XM_017019262.3 → XP_016874751.1 insulin-like growth factor I isoform X2
XM_017019259.2 → XP_016874748.1 insulin-like growth factor I isoform X1