NACC1 (nucleus accumbens associated 1, BEN and BTB (POZ) domain containing)

2012-05-01   Kai Lee Yap , Ie-Ming Shih 

Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Identity

HGNC
LOCATION
19p13.2
LOCUSID
ALIAS
BEND8,BTBD14B,BTBD30,NAC-1,NAC1,NECFM
FUSION GENES

DNA/RNA

Description

The NACC1 gene is encoded by 5 exons spanning 5958 base pairs that are located on chromosome 19p13.13.

Transcription

4556 bp linear mRNA. The coding sequence (1584 bp) is from 169-1752 bp.

Proteins

Description

NAC1 consists of 527 amino acids and the protein is predicted to have a molecular weight of 57258 Da (Stead et al., 2009). Comprising of a N terminal BTB/POZ domain and the C terminal BEN domain, NAC1 is missing a Zinc Finger domain unlike many members of the BTB/POZ family. The homodimerization of NAC1 mediated by the BTB domain is thought to be essential for its functional activities (Nakayama et al., 2006). The newly defined BEN domain may mediate protein-DNA interactions (Abhiman et al., 2008), however it remains to be investigated if NAC1 is indeed a DNA binding protein.

Expression

Expressed in Arabidopsis root as a transcription activator, found in nuclear accumbens of neuronal tissues and overexpressed in various human neoplastic diseases (Cha et al., 1997; Xie et al., 2002; Guo et al., 2005; Nakayama et al., 2006; Shen et al., 2007; Nakayama et al., 2007; Yeasmin et al., 2008; Mackler et al., 2008; Ishibashi et al., 2009; Korutla et al., 2009; Ishikawa et al., 2010; Yeasmin et al., 2011).

Localisation

Nucleus and cytoplasm. Dynamic changes in subcellular localization of NAC1 at the different phases of cell cycle progression were documented. In non-mitotic cells, NAC1 accumulated in distinct nuclear punctate bodies. During mitosis, these punctate nuclear bodies dissolve into a diffuse pattern of distribution in the cytoplasm. NAC1 nuclear bodies reappeared once mitosis was completed and the nuclear membrane reformed. (Wu et al., 2011).

Function

First identified as a novel transcript in the nucleus-accumbens of cocaine-addicted rats (Cha et al., 1997), NAC1 was known as a transcriptional corepressor (Korutla et al., 2009) with well defined functions in the murine neurologic physiological pathways (Shen et al., 2007; Mackler et al., 2008) and Arabidopsis root development (Xie et al., 2002; Guo et al., 2005). The role of NAC1 in human cancer was unknown. Preliminary studies of SAGE (Serial Analysis of Gene Expression) libraries were conducted to elucidate the role of NAC1 in the pathogenesis of human cancers and had revealed the higher expression levels of NAC1 in tumor samples as compared to the normal tissues in various cancer types such as pancreas, liver, and breast (Nakayama et al., 2006). Following that, detailed gene expression studies were undertaken in patient tumor samples and characterized the overexpression of NAC1 in cervical carcinoma and ovarian high-grade serous carcinoma, one of the most lethal neoplastic diseases in women (Nakayama et al., 2006; Nakayama et al., 2007; Yeasmin et al., 2008; Ishibashi et al., 2009; Jinawath et al., 2009; Nakayama et al., 2010; Ishikawa et al., 2010; Shih et al., 2011; Yeasmin et al., 2011). Amplification of NACC1 has also been recently reported in ovarian cancer, and analysis of The Cancer Genome Atlas data set revealed that NACC1 was one of the top potential "driver" genes that showed the highest correlation between DNA and RNA copy number in ovarian high-grade serous carcinomas (Shih et al., 2011). Additionally, NAC1 up-regulation is associated with disease aggressiveness and contributes to the development of chemo-resistance (Nakayama et al., 2006; Jinawath et al., 2009; Nakayama et al., 2010; Zhang et al., 2012). NAC1 enables the survival and growth of ovarian cancer cells by regulating several downstream targets including those involved in Gadd45 cell survival pathway (Nakayama et al., 2007; Jinawath et al., 2009), fatty acid metabolism (Ueda et al., 2010), and HMGB-1 mediated autophagic response (Zhang et al., 2012). NAC1 function has also been demonstrated to be essential for the migration of ovarian and melanoma cancer cells (Yamazaki et al., 2005; Nakayama et al., 2010). Mouse tumor xenograft studies illustrated the in vivo therapeutic potential of inactivating Nac1 function; as such manipulation in SKOV3 ovarian cancer cells and HeLa cervical cancer cells was demonstrated to be sufficient to inhibit the growth of tumor xenografts (Nakayama et al., 2006). Nac1 is more recently associated with maintenance of the pluripotency of mouse embryonic stem cells through its interaction with Nanog (Wang et al., 2006; Ma et al., 2009).
Atlas Image
Functions of NAC1 in various systems and pathways.

Homology

BEN1 domain, BTB/POZ domain.

Implicated in

Entity name
Ovarian serous carcinoma
Disease
NACC1 is highly overexpressed in ovarian carcinomas. High NAC1 expression is correlated with early tumor recurrence (Nakayama et al., 2006). Nakayama et al. found there is significant correlation between poor prognosis and the expression of NAC1 in patients who received taxol therapy. In addition, high immunoreactivity to NAC1 in the primary ovarian tumor is able to predict early tumor recurrence. The mechanism of over expression of NAC1 in ovarian serous carcinoma is by amplication of the gene locus ch19p13.2 carrying the NACC1 gene (Shih et al., 2011). NAC1 function is important for the survival and proliferation of ovarian cancer cells, and increases their migration and motility (Nakayama et al., 2010). Zhang et al. found that NAC1 is also implicated in autophagic response in the ovarian cancer cell line, which may contribute to the development of chemoresistance (Zhang et al., 2012).
Entity name
Cervical carcinomas
Disease
Using immunohistochemistry, Yeasmin et al. found that NACC1 is more frequently overexpressed in cervical adenocarcinomas and adenosquamous carcinomas as compared to squamous cell carcinomas (Yeasmin et al., 2008). In squamous cell carcinomas that have overexpression of NAC1, NACC1 gene amplication was detected, and positive NAC1 expression is linked to shorter overall survival. NAC1-silenced cancer cells undergo growth inhibition, increased apoptosis, decreased proliferation, cellular migration and invasion.
Entity name
Endometrial carcinomas
Disease
NAC1 was found to be overexpressed in the normal endometrium in the early and mid proliferative phases by the actions of circulating estrogen (Ishibashi et al., 2009). Ishikawa et al. found that there were significant correlations between positive NAC1 expression and pathological grade in endometrial carcinomas (Ishikawa et al., 2010). Endometrial carcinomas with NAC1 overexpression were found to be clinically aggressive, high-grade carcinomas. However unexpectedly they also found that during the progression from normal endometrium to hyperplasia and finally to carcinoma, there is a stepwise reduction in NAC1 protein expression. It was proposed that this might be related to loss of estrogen signaling in development of endometrial cancers (Ishibashi et al., 2009).

Bibliography

Pubmed IDLast YearTitleAuthors
182037712008BEN: a novel domain in chromatin factors and DNA viral proteins.Abhiman S et al
92785211997NAC-1, a rat brain mRNA, is increased in the nucleus accumbens three weeks after chronic cocaine self-administration.Cha XY et al
158296032005MicroRNA directs mRNA cleavage of the transcription factor NAC1 to downregulate auxin signals for arabidopsis lateral root development.Guo HS et al
191881502009Expression of a BTB/POZ protein, NAC1, is essential for the proliferation of normal cyclic endometrial glandular cells and is up-regulated by estrogen.Ishibashi M et al
203727822010NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma.Ishikawa M et al
193054292009NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway.Jinawath N et al
191213542009NAC1, a POZ/BTB protein that functions as a corepressor.Korutla L et al
193667002009The C-terminal pentapeptide of Nanog tryptophan repeat domain interacts with Nac1 and regulates stem cell proliferation but not pluripotency.Ma T et al
179453612008Requirement for the POZ/BTB protein NAC1 in acute but not chronic psychomotor stimulant response.Mackler S et al
208697612010Biological role and prognostic significance of NAC1 in ovarian cancer.Nakayama K et al
176996722007NAC1 regulates the recruitment of the proteasome complex into dendritic spines.Shen H et al
212402552011Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma.Shih IeM et al
194073732009Structure of the human Nac1 POZ domain.Stead MA et al
205087252010Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas.Ueda SM et al
170934072006A protein interaction network for pluripotency of embryonic stem cells.Wang J et al
213010572011Cell cycle-dependent alteration in NAC1 nuclear body dynamics and morphology.Wu PH et al
122266652002SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals.Xie Q et al
160535082005Regulation of cancer cell motility through actin reorganization.Yamazaki D et al
218891862012Biological and clinical significance of NAC1 expression in cervical carcinomas: a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas.Yeasmin S et al
217434892012NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response.Zhang Y et al

Other Information

Locus ID:

NCBI: 112939
MIM: 610672
HGNC: 20967
Ensembl: ENSG00000160877

Variants:

dbSNP: 112939
ClinVar: 112939
TCGA: ENSG00000160877
COSMIC: NACC1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000160877ENST00000292431Q96RE7
ENSG00000160877ENST00000292431A0A024R7E0
ENSG00000160877ENST00000585663K7ELC5
ENSG00000160877ENST00000586171K7ENW4

Expression (GTEx)

0
10
20
30
40
50
60
70

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
217434892012NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response.51
171304572006A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival.47
193054292009NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway.35
178047172007NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor.29
212402552011Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma.21
218891862012Biological and clinical significance of NAC1 expression in cervical carcinomas: a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas.20
184833832008A BTB/POZ gene, NAC-1, a tumor recurrence-associated gene, as a potential target for Taxol resistance in ovarian cancer.19
191213542009NAC1, a POZ/BTB protein that functions as a corepressor.19
183471692008Expression of the bric-a-brac tramtrack broad complex protein NAC-1 in cervical carcinomas seems to correlate with poorer prognosis.18
208697612010Biological role and prognostic significance of NAC1 in ovarian cancer.18

Citation

Kai Lee Yap ; Ie-Ming Shih

NACC1 (nucleus accumbens associated 1, BEN and BTB (POZ) domain containing)

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/44511/nacc1