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). |
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| Functions of NAC1 in various systems and pathways. |
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Homology | BEN1 domain, BTB/POZ domain. |
BEN: a novel domain in chromatin factors and DNA viral proteins. |
Abhiman S, Iyer LM, Aravind L. |
Bioinformatics. 2008 Feb 15;24(4):458-61. Epub 2008 Jan 18. |
PMID 18203771 |
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NAC-1, a rat brain mRNA, is increased in the nucleus accumbens three weeks after chronic cocaine self-administration. |
Cha XY, Pierce RC, Kalivas PW, Mackler SA. |
J Neurosci. 1997 Sep 15;17(18):6864-71. |
PMID 9278521 |
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MicroRNA directs mRNA cleavage of the transcription factor NAC1 to downregulate auxin signals for arabidopsis lateral root development. |
Guo HS, Xie Q, Fei JF, Chua NH. |
Plant Cell. 2005 May;17(5):1376-86. Epub 2005 Apr 13. |
PMID 15829603 |
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Expression 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, Nakayama K, Yeasmin S, Katagiri A, Iida K, Nakayama N, Miyazaki K. |
Clin Cancer Res. 2009 Feb 1;15(3):804-11. |
PMID 19188150 |
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NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma. |
Ishikawa M, Nakayama K, Yeasmin S, Katagiri A, Iida K, Nakayama N, Miyazaki K. |
Int J Oncol. 2010 May;36(5):1097-103. |
PMID 20372782 |
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NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway. |
Jinawath N, Vasoontara C, Yap KL, Thiaville MM, Nakayama K, Wang TL, Shih IM. |
Oncogene. 2009 May 7;28(18):1941-8. Epub 2009 Mar 23. |
PMID 19305429 |
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NAC1, a POZ/BTB protein that functions as a corepressor. |
Korutla L, Wang P, Jackson TG, Mackler SA. |
Neurochem Int. 2009 Mar-Apr;54(3-4):245-52. Epub 2008 Dec 13. |
PMID 19121354 |
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The C-terminal pentapeptide of Nanog tryptophan repeat domain interacts with Nac1 and regulates stem cell proliferation but not pluripotency. |
Ma T, Wang Z, Guo Y, Pei D. |
J Biol Chem. 2009 Jun 12;284(24):16071-81. Epub 2009 Apr 14. |
PMID 19366700 |
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Requirement for the POZ/BTB protein NAC1 in acute but not chronic psychomotor stimulant response. |
Mackler S, Pacchioni A, Degnan R, Homan Y, Conti AC, Kalivas P, Blendy JA. |
Behav Brain Res. 2008 Feb 11;187(1):48-55. Epub 2007 Sep 2. |
PMID 17945361 |
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Biological role and prognostic significance of NAC1 in ovarian cancer. |
Nakayama K, Rahman MT, Rahman M, Yeasmin S, Ishikawa M, Katagiri A, Iida K, Nakayama N, Miyazaki K. |
Gynecol Oncol. 2010 Dec;119(3):469-78. Epub 2010 Sep 24. |
PMID 20869761 |
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NAC1 regulates the recruitment of the proteasome complex into dendritic spines. |
Shen H, Korutla L, Champtiaux N, Toda S, LaLumiere R, Vallone J, Klugmann M, Blendy JA, Mackler SA, Kalivas PW. |
J Neurosci. 2007 Aug 15;27(33):8903-13. |
PMID 17699672 |
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Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma. |
Shih IeM, Nakayama K, Wu G, Nakayama N, Zhang J, Wang TL. |
Mod Pathol. 2011 May;24(5):638-45. Epub 2011 Jan 14. |
PMID 21240255 |
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Structure of the human Nac1 POZ domain. |
Stead MA, Carr SB, Wright SC. |
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 May 1;65(Pt 5):445-9. Epub 2009 Apr 24. |
PMID 19407373 |
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Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas. |
Ueda SM, Yap KL, Davidson B, Tian Y, Murthy V, Wang TL, Visvanathan K, Kuhajda FP, Bristow RE, Zhang H, Shih IeM. |
J Oncol. 2010;2010:285191. Epub 2010 May 19. |
PMID 20508725 |
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A protein interaction network for pluripotency of embryonic stem cells. |
Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH. |
Nature. 2006 Nov 16;444(7117):364-8. Epub 2006 Nov 8. |
PMID 17093407 |
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Cell cycle-dependent alteration in NAC1 nuclear body dynamics and morphology. |
Wu PH, Hung SH, Ren T, Shih IeM, Tseng Y. |
Phys Biol. 2011 Feb;8(1):015005. Epub 2011 Feb 7. |
PMID 21301057 |
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SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals. |
Xie Q, Guo HS, Dallman G, Fang S, Weissman AM, Chua NH. |
Nature. 2002 Sep 12;419(6903):167-70. |
PMID 12226665 |
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Regulation of cancer cell motility through actin reorganization. |
Yamazaki D, Kurisu S, Takenawa T. |
Cancer Sci. 2005 Jul;96(7):379-86. |
PMID 16053508 |
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Biological and clinical significance of NAC1 expression in cervical carcinomas: a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas. |
Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Otuski Y, Kobayashi H, Nakayama S, Miyazaki K. |
Hum Pathol. 2012 Apr;43(4):506-19. Epub 2011 Sep 1. |
PMID 21889186 |
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NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response. |
Zhang Y, Cheng Y, Ren X, Zhang L, Yap KL, Wu H, Patel R, Liu D, Qin ZH, Shih IM, Yang JM. |
Oncogene. 2012 Feb 23;31(8):1055-64. doi: 10.1038/onc.2011.290. Epub 2011 Jul 11. |
PMID 21743489 |
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