TAC1 (tachykinin, precursor 1)

2009-06-01 Philip K Lim , Shyam A Patel , Pranela Rameshwar Affiliation

University of Medicine, Dentistry of New Jersey - New Jersey Medical School,Newark, New Jersey, USA

Identity

HGNC

TAC1

LOCATION

7q21.3

LOCUSID

6863

ALIAS

Hs.2563,NK2,NKNA,NPK,TAC2

DNA/RNA

Description

The TAC1 gene maps (Homo sapiens) to NC_000007.12 in the region between 97199311 and 97207720 on the plus strand and spans 8410 bp.

Transcription

4 transcript variants:
alpha (1134 bp); open reading frame from bp 247-582
-lacks exon 6
-encodes substance P on exon 3
beta (1188 bp); open reading frame from bp 247-636
-encodes the full-length version of Tac1
-encodes substance P, neurokinin A, neuopeptide K
delta (1089 bp); open reading frame from bp 247-537
-lacks exons 4 and 6
-encodes substance P on exon 3
gamma (1143 bp); open reading frame from bp 247-591
-lacks exon 4
-encodes substance P, neurokinin A

Proteins

Note

The TAC1 gene encodes multiple transcripts through post-translational modifications. Each encodes peptides belonging to the tachykinin family of peptides. The major peptides produced from the TAC1 transcripts are substance P and neurokinin A. Others include neuropeptide K, and neuropeptide gamma. The tachykinins exert multiples functions such as neurotransmission, immune modulation and hematopoietic regulation. TAC1 encodes peptides that target nerve receptors, immune cells, stem cells, hematopoietic cells and smooth muscle cells. They function in vasodilatory responses; act as secretagogues and can induce behavioral responses.

Description

4 peptides:
alpha: 111 aa
-comprises substance P
beta: 129 aa
-comprises substance P, neurokinin A, neuropeptide K
delta: 96 aa
-comprises substance P
gamma: 114 aa
-comprises neuropeptide gamma, substance P, neurokinin A.

Expression

Expressed by various immune and neuronal cells.
TAC1 expression in the setting of osteoarthritis can be induced by mechanical stimulation (Howard et al., 2008).
TAC1 expression is also regulated by microRNAs in neurons derived from human mesenchymal stem cells (Greco et al., 2007). This occurs by binding of miRNA-13-a, miRNA206 and miRNA302a to the Tac1 3UTR.
HIV1 infection resulted in increase production of TAC1 peptide (substance P). The source of substance P has been identified as monocytes-derived macrophages from placenta cord blood and adult peripheral blood. The production of substance P correlates with HIV 1 infection (Douglas et al., 2002).

Localisation

Secreted peptide.

Function

TAC1 peptides function in both pathologic and physiologic processes. These include hematopoiesis, gastrointestinal secretory processes, respiratory patterns, calcium signaling, neuropeptide signaling, pain, synaptic transmission, insemination (Murthy et al., 2008; David et al., 2009); inflammatory response, autism, and pulmonary infection (Marui et al., 2007; Grissell et al., 2007).
In normal respiratory development, TAC1 appears to be a crucial gene, exerting plasticity during development (Berner et al., 2007).
TAC1 is involved in hematopoietic regulation. The mRNA is targeted by RNA-binding protein that confers translational control, which could be negatively regulated by cytokines with hematopoietic stimulator properties (Murthy et al., 2008).
TAC1 has been implicated in macrophage and monocyte functions (Chernova et al., 2009).

Homology

Homo sapiens TAC1 shares sequence homology with mouse and rat sequences.

Implicated in

Entity name

Breast Cancer

Note

A gene expression signature for breast cancer has been shown to involve TAC1 (Ellsworth et al., 2009).

Prognosis

TAC1 expression occurs in breast cancer and is directly proportional to aggressiveness of the cancer and thus, TAC1 may also be a prognostic factor in breast cancer (Ellsworth et al., 2009; Reddy et al., 2009).

Oncogenesis

TAC1 expression favors breast cancer cell entry into the bone marrow during stage IV disease (Reddy et al., 2009). TAC1 regulates the interaction between CXCL12 and its receptor, CXCR4 in the interaction between breast cancer and mesenchymal stem cells (Corcoran et al., 2008).
The TAC1 gene products, substance P and neurokinin A, and neurokinin receptor antagonists have been shown to have anti-proliferative effects on breast cancer cells (Rameswhar et al., 1996; Singh et al., 2000).

Entity name

Colon cancer

Note

Substance P, the major peptide encoded by the TAC1 gene, is mitogenic to colon cancer. Its action on the cancer cells appears to be autocrine since NK1 antagonist has been shown to mediate anti-tumor activity (Rosso et al., 2008). On the other hand, Substance P also enhances the expansion of lymphokine-activated killer cells against colon cancer cells (Flageole et al., 1992). These two properties of substance P appear paradoxical. Thus, targeted therapy will need to balance the immune-enhancing effects with the tumor promoting functions of substance.

Prognosis

In Dukes stage A/B cancers, TAC1 methylation levels were significantly higher than in Dukes stage C/D cancers (Mori et al., 2006).

Oncogenesis

TAC1 was found to be silenced via promoter methylation in primary colon cancer and may lead to early stage carcinogenesis by aiding tumor cells to escape immune surveillance and autocrine growth-inhibitory signaling (Mori et al., 2006).

Entity name

Esophageal cancer

Prognosis

Promoter hypermethylation of TAC1 confers poor prognosis in esophageal cancer (Jin et al., 2007).

Oncogenesis

TAC1 promoter hypermethylation has been suggested to be a putative marker for esophageal carcinoma (Jin et al., 2007).

Entity name

Gastric adenocarcinoma

Oncogenesis

Promoter hypermethylation of TAC1 has also been found in gastric adenocarcinoma (David et al., 2009).

Entity name

Multiple Sclerosis

Note

The genetic region surrounding TAC1 may be unstable and has been associated with increased susceptibility to multiple sclerosis (Vandenbroeck et al., 2002).

Entity name

Narcolepsy

Note

TAC1 and other related peptides have been associated with narcolepsy. Stimulation by amphetamines promotes increased TAC1 expression (Lindberg et al., 2007).

Bibliography

Pubmed ID	Last Year	Title	Authors
17525292	2007	Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene.	Berner J et al
18835883	2009	Substance P (SP) enhances CCL5-induced chemotaxis and intracellular signaling in human monocytes, which express the truncated neurokinin-1 receptor (NK1R).	Chernova I et al
18575622	2008	Mesenchymal stem cells in early entry of breast cancer into bone marrow.	Corcoran KE et al
19046942	2009	Aberrant silencing of the endocrine peptide gene tachykinin-1 in gastric cancer.	David S et al
19112599	2009	A gene expression signature that defines breast cancer metastases.	Ellsworth RE et al
1279274	1992	Substance P increases in vitro lymphokine-activated-killer (LAK) cell cytotoxicity against fresh colorectal cancer cells.	Flageole H et al
17855557	2007	MicroRNAs regulate synthesis of the neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells.	Greco SJ et al
17358043	2007	Reduced toll-like receptor 4 and substance P gene expression is associated with airway bacterial colonization in children.	Grissell TV et al
11919172	2002	HIV enhances substance P expression in human immune cells.	Ho WZ et al
18990442	2008	Mechanical stimulation induces preprotachykinin gene expression in osteoarthritic chondrocytes which is correlated with modulation of the transcription factor neuron restrictive silence factor.	Howard MR et al
17975140	2007	Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer.	Jin Z et al
17521418	2007	Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.	Lindberg J et al
17376622	2007	Tachykinin 1 (TAC1) gene SNPs and haplotypes with autism: a case-control study.	Marui T et al
16952549	2006	A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer.	Mori Y et al
18061399	2008	Tac1 regulation by RNA-binding protein and miRNA in bone marrow stroma: Implication for hematopoietic activity.	Murthy RG et al
8704207	1996	Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma.	Rameshwar P et al
19246391	2009	RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells.	Reddy BY et al
18781096	2008	The NK-1 receptor is expressed in human primary gastric and colon adenocarcinomas and is involved in the antitumor action of L-733,060 and the mitogenic action of substance P on human gastrointestinal cancer cell lines.	Rosso M et al
10618428	2000	Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis.	Singh D et al
11960650	2002	Chromosome 7q21-22 and multiple sclerosis: evidence for a genetic susceptibility effect in vicinity to the protachykinin-1 gene.	Vandenbroeck K et al

Other Information

Locus ID:

NCBI: 6863
MIM: 162320
HGNC: 11517
Ensembl: ENSG00000006128

Variants:

dbSNP: 6863
ClinVar: 6863
TCGA: ENSG00000006128
COSMIC: TAC1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000006128	ENST00000319273	P20366
ENSG00000006128	ENST00000346867	P20366
ENSG00000006128	ENST00000350485	P20366

Expression (GTEx)

100

150

200

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Signal Transduction	REACTOME	R-HSA-162582
Signaling by GPCR	REACTOME	R-HSA-372790
GPCR ligand binding	REACTOME	R-HSA-500792
Class A/1 (Rhodopsin-like receptors)	REACTOME	R-HSA-373076
Peptide ligand-binding receptors	REACTOME	R-HSA-375276
Tachykinin receptors bind tachykinins	REACTOME	R-HSA-380095
GPCR downstream signaling	REACTOME	R-HSA-388396
G alpha (q) signalling events	REACTOME	R-HSA-416476
Gastrin-CREB signalling pathway via PKC and MAPK	REACTOME	R-HSA-881907

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
17703412	2007	Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.	100
19874574	2009	Genetical genomic determinants of alcohol consumption in rats and humans.	93
19598235	2009	Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.	92
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
16952549	2006	A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer.	69
14532289	2003	Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization.	59
21091716	2011	Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation.	44
17855557	2007	MicroRNAs regulate synthesis of the neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells.	40
17264209	2007	Substance P mediates antiapoptotic responses in human colonocytes by Akt activation.	39
19695094	2009	Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc.	36

Citation

Philip K Lim ; Shyam A Patel ; Pranela Rameshwar

TAC1 (tachykinin, precursor 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-06-01

Online version: http://atlasgeneticsoncology.org/gene/44483/tac1-(tachykinin-precursor-1)