NAMPT (nicotinamide phosphoribosyltransferase)

2012-06-01   Vassiliki Koumaki , Maria Dalamaga 

Identity

HGNC
LOCATION
7q22.3
LOCUSID
ALIAS
1110035O14Rik,PBEF,PBEF1,VF,VISFATIN
FUSION GENES

DNA/RNA

Atlas Image
Genomic structure of NAMPT. Orange boxes indicate exons and purple boxes indicate untranslated regions.

Description

The human NAMPT gene spans a length of 36908 bp. The NAPMT structural gene is composed of 11 exons and 10 introns.

Transcription

Transcription produces 19 different mRNAs, 14 alternatively spliced variants and 5 unspliced forms. There are 5 probable alternative promoters, 6 non overlapping alternative last exons and 13 alternative polyadenylation sites. The mRNAs appear to differ by truncation of the 3 end, presence or absence of 2 cassette exons, overlapping exons with different boundaries, alternative splicing or retention of 4 introns (Zhang et al., 2011).

Pseudogene

This gene has a pseudogene on chromosome 10 (provided by RefSeq 2011).

Proteins

Description

The reference human NAMPT protein sequence (NP_005737) consists of 491 amino acids.

Expression

NAMPT is expressed in human heart, brain, placenta, lungs, liver, skeletal muscle, kidney and pancreas with the maximum amount in muscle tissue (Samal et al.,1994).

Localisation

NAMPT is localized both in the nucleus and the cytosplasm (Kitani et al., 2003).

Function

The three major functions of NAMPT: growth factor, cytokine and nicotinamide phosphoribosyltransferase. Accumulating evidence suggests that NAMPT can function as a growth factor or a cytokine though the underlying molecular mechanisms remain to be established. It is beyond any dispute that NAMPT can function as a nicotinamide phosphoribosyltransferase (Zhang et al., 2011).
Enzymatic activity: because of its pivotal role in the recycling pathway allowing NAD generation from nicotinamide, NAMPT occupies a central position in controlling the activity of several NAD-dependent enzymes (Gallí et al., 2010). NAD, a universal energy-and signal-carrying molecule and its phosphorylated form, NADP, are required in several intracellular processes such as redox reactions, DNA repair, G-protein coupled receptor signaling, intra-cellular calcium-mobilizing molecules, transcriptional regulation, mono-adenosine diphosphate (ADP)-ribosylation in immune response, and activity of poly-ADP ribosyltransferases and deacetylases (sirtuins) with roles in regulating cell survival and cytokine responses (Garten et al., 2009). Under the influence of NAMPT, adequate levels of NAD control SIRT-6 (sirtuin) activity, which in turn positively regulates TNF-α mRNA translation favoring cell survival (Gallí et al., 2010). NAMPT activity enhances cellular proliferation, tips the balance toward cellular survival following a genotoxic insult and controls the circadian clock machinery of some key transcriptions factors (Garten et al., 2009; Moschen et al., 2010).

Homology

Significant sequence homology has been shared among prokaryotic organisms such as the bacterium Haemophilus ducreyi, primitive metazoan such as marine sponge, and humans (Martin et al., 2001). Amino acid sequence alignment revealed that the NAMPT gene is evolutionarily highly conserved, with the canine NAMPT protein sequence 96% identical to human NAMPT and 94% identical to both murine and rat PBEF counterparts (McGlothlin et al., 2005).

Mutations

Note

Homozygous deletion confers embryonic lethality in mouse (Ye at al., 2005).
Up to June 2012 NCBI dbSNP reports 730 SNPs in the human NAMPT gene. Functional consequences of most of these SNPs are currently unknown (Zhang et al., 2011).
Acquired resistance to inhibitors of NAMPT has been associated with mutations of NAMPT located in the vicinity of the active site or in the dimer interface of NAMPT (Olesen et al., 2010).

Implicated in

Entity name
Various diseases
Note
The dysregulation of NAMPT gene as well as abnormalities in circulating NAMPT levels have been implicated in the susceptibility and pathogenesis of a number of human diseases and pathologic conditions given NAMPTs pleiotropic physiological functions. NAMPT has been implicated in cancer as described below, diabetes, obesity, aging, atherosclerosis, sepsis, acute lung injury, rheumatoid arthritis, etc (Zhang et al., 2011).
Entity name
Colorectal cancer (CC)
Note
NAMPT expression was increased in primary colorectal cancer comparing to normal control mucosa using the suppression subtractive hybridization technique to identify new candidate genes in cancer (Hufton et al., 1999). This observation was later confirmed at tissue and protein level by Western blotting and immune-histochemical analyses (Van Beijnum et al., 2002). Serum Nampt levels were significantly higher in 115 CC patients than in 115 age-, gender- and body mass index (BMI)-matched controls both in univariate (p
Prognosis
Serum Nampt levels may represent a promising biomarker of CC malignant potential and stage progression. Circulating Nampt gradually increased with tumor stage progression (p
Entity name
Breast cancer (BC)
Note
NAMPT is expressed in BC tissues, in MCF-7 BC cells and in doxorubicin-responsive BC (Folgueira et al., 2005; Gallí et al., 2010; Zhang et al., 2011; Moschen et al., 2010; Garten et al., 2009). Additionally, Nampt is present in bovine mammary epithelium, lactating mammary glands, and milk (Yonezawa et al., 2006). NAMPT stimulated the proliferation and DNA synthesis rate of MCF-7 human BC cells (Kim et al., 2010). More specifically, NAMPT upregulated mRNA levels of cyclin D1 and cdk2, well-known regulators for the G1-S progression (Kim et al., 2010). Circulating levels of Nampt were significantly elevated in women suffering from postmenopausal BC than in controls independently from known risk factors of BC, anthropometric and metabolic parameters as well as serum concentrations of leptin and adiponectin (Dalamaga et al., 2011). Stratification by BMI depicted that the association of serum Nampt with PBC risk was more pronounced among overweight/obese postmenopausal women after adjustment for the aforementioned parameters (Dalamaga et al., 2011; Dalamaga et al., 2012b).
Prognosis
High NAMPT expression in BC tissues was reported to be associated with more malignant cancer behavior as well as adverse prognosis (Lee et al., 2011). In the high NAMPT expression group, the majority of patients were estrogen and progesterone negative (Lee et al., 2011). Serum Nampt could be used as potential diagnostic and prognostic biomarker in the armamentarium of BC monitoring and management. In postmenopausal women, circulating Nampt could provide additional information in conjunction with tumor markers CA 15-3 and carcinoembryonic antigen, particularly in discriminating early stage cases and estrogen/progesterone negative breast tumors (Dalamaga et al., 2012b). In multivariable regression analysis, the most significant predictors/determinants of serum Nampt levels were the hormone receptor status, the late stage of PBC and the lymph node involvement (Dalamaga et al., 2012b).
Entity name
Gastric cancer (GC)
Note
Using real-time PCR and Western blotting, NAMPT was overexpressed at the mRNA and protein levels in gastric cancer cells and human gastric cancer tissues (Bi et al., 2011). The specific NAMPT inhibitor FK866 repressed gastric cancer cell proliferation in vitro (Bi et al., 2011). Serum Nampt levels were significantly higher in 156 GC patients than in 156 age- and gender-matched controls using multivariable analysis (p= 0.0013) (Nakajima et al., 2009).
Prognosis
Nampt may be good biomarker of GC as its circulating levels gradually increased with stage progression (P
Entity name
Prostate cancer (PC)
Oncogenesis
In prostate carcinogenesis, NAMPT increased PC3 cell proliferation activating the mitogen-activated protein kinases (MAPKs) ERK-1/ERK-2 and p38 signaling pathways (Patel et al., 2010). NAMPT promoted the activity and expression of MMP-2/MMP-9 which represent important proteases involved in the breakdown of the extracellular matrix, indicating a possible role for NAMPT in PC metastasis (Patel et al., 2010). Upregulation of NAMPT expression occurs early in prostate neoplasia (Wang et al., 2011). Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H2O2 or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown (Wang et al., 2011).
Entity name
Brain tumors
Note
Increased NAMPT expression was found in glioblastoma samples using cDNA microarray based expression profiling, real-time RT-qPCR and immunohistochemical staining on an independent set of brain tumor samples (Reddy et al., 2008). APO866, a NAMPT inhibitor, is a potent growth inhibitor against glioblastoma through targeting NAMPT. APO866 depleted intracellular NAD, caused marked inhibition of ERK activation and induced G2/M cell-cycle arrest in C6 glioblastoma cells (Zhang et al., 2012).
Prognosis
Serum Nampt levels may be a potential serum biomarker for malignant astrocytoma and prognostic indicator in glioblastoma (Reddy et al., 2008).
Entity name
Ovarian cancer
Note
NAMPT protein expression is significantly increased in ovarian serous adenocarcinoma comparing to benign ovarian tissue using tissue microarray and the avidin-biotin complex immuno-histochemical technique (Shackelford et al., 2010).
Entity name
Esophageal cancer
Prognosis
Using quantitative one-step real time RT-PCR, circulating Nampt mRNAs in postoperative esophagectomy patients were upregulated adjusting for other factors (p
Entity name
Lymphoma
Note
NAMPT expression was investigated in 53 samples of malignant lymphomas (

Bibliography

Pubmed IDLast YearTitleAuthors
217439672011Overexpression of Nampt in gastric cancer and chemopotentiating effects of the Nampt inhibitor FK866 in combination with fluorouracil.Bi TQ et al
225471602012The role of adiponectin in cancer: a review of current evidence.Dalamaga M et al
162438172005Gene expression profile associated with response to doxorubicin-based therapy in breast cancer.Folgueira MA et al
200288512010The nicotinamide phosphoribosyltransferase: a molecular link between metabolism, inflammation, and cancer.Gallí M et al
191090342009Nampt: linking NAD biology, metabolism and cancer.Garten A et al
106016421999A profile of differentially expressed genes in primary colorectal cancer using suppression subtractive hybridization.Hufton SE et al
208482322010Visfatin stimulates proliferation of MCF-7 human breast cancer cells.Kim JG et al
127822932003Growth phase-dependent changes in the subcellular localization of pre-B-cell colony-enhancing factor.Kitani T et al
217849592011High visfatin expression in breast cancer tissue is associated with poor survival.Lee YC et al
111579282001Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence.Martin PR et al
159341742005Molecular cloning and characterization of canine pre-B-cell colony-enhancing factor.McGlothlin JR et al
203706722010Pre-B cell colony enhancing factor/NAMPT/visfatin in inflammation and obesity-related disorders.Moschen AR et al
203316312010Adipocytokines as new promising markers of colorectal tumors: adiponectin for colorectal adenoma, and resistin and visfatin for colorectal cancer.Nakajima TE et al
214922302011Expression patterns of nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase in human malignant lymphomas.Olesen UH et al
211440002010Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase.Olesen UH et al
198192772010A novel role for the adipokine visfatin/pre-B cell colony-enhancing factor 1 in prostate carcinogenesis.Patel ST et al
187284032008PBEF1/NAmPRTase/Visfatin: a potential malignant astrocytoma/glioblastoma serum marker with prognostic value.Reddy PS et al
82898181994Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor.Samal B et al
206067332010Over-expression of nicotinamide phosphoribosyltransferase in ovarian cancers.Shackelford RE et al
209697442010Prognostic impact of clinical course-specific mRNA expression profiles in the serum of perioperative patients with esophageal cancer in the ICU: a case control study.Takahashi S et al
122099882002Target validation for genomics using peptide-specific phage antibodies: a study of five gene products overexpressed in colorectal cancer.Van Beijnum JR et al
161882812005Pre-B-cell-colony-enhancing factor is critically involved in thrombin-induced lung endothelial cell barrier dysregulation.Ye SQ et al
171235172006Visfatin is present in bovine mammary epithelial cells, lactating mammary gland and milk, and its expression is regulated by cAMP pathway.Yonezawa T et al
221406072011Nicotinamide Phosphoribosyltransferase in Human Diseases.Zhang LQ et al
221193812012Anti-proliferation effect of APO866 on C6 glioblastoma cells by inhibiting nicotinamide phosphoribosyltransferase.Zhang LY et al

Other Information

Locus ID:

NCBI: 10135
MIM: 608764
HGNC: 30092
Ensembl: ENSG00000105835

Variants:

dbSNP: 10135
ClinVar: 10135
TCGA: ENSG00000105835
COSMIC: NAMPT

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000105835ENST00000222553P43490
ENSG00000105835ENST00000222553A0A024R718
ENSG00000105835ENST00000354289A0A0C4DFS8
ENSG00000105835ENST00000417537C9JF35
ENSG00000105835ENST00000424768C9JG65

Expression (GTEx)

0
100
200
300
400
500
600

Pathways

PathwaySourceExternal ID
Nicotinate and nicotinamide metabolismKEGGko00760
Nicotinate and nicotinamide metabolismKEGGhsa00760
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Metabolic pathwaysKEGGhsa01100
Circadian ClockREACTOMER-HSA-400253
BMAL1:CLOCK,NPAS2 activates circadian gene expressionREACTOMER-HSA-1368108
MetabolismREACTOMER-HSA-1430728
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of water-soluble vitamins and cofactorsREACTOMER-HSA-196849
Nicotinate metabolismREACTOMER-HSA-196807
Nicotinamide salvagingREACTOMER-HSA-197264

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
178896522007Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival.376
172374242007Visfatin, an adipocytokine with proinflammatory and immunomodulating properties.191
151240232004Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis.152
164961212006Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin.119
161863922005Plasma visfatin concentrations and fat depot-specific mRNA expression in humans.107
173077302007Extension of human cell lifespan by nicotinamide phosphoribosyltransferase.107
262152592015Physiological and pathophysiological roles of NAMPT and NAD metabolism.100
162343022006Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus.97
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
209569372011NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response.80

Citation

Vassiliki Koumaki ; Maria Dalamaga

NAMPT (nicotinamide phosphoribosyltransferase)

Atlas Genet Cytogenet Oncol Haematol. 2012-06-01

Online version: http://atlasgeneticsoncology.org/gene/43890/nampt-(nicotinamide-phosphoribosyltransferase)