| Description | The wild type LDOC1 is a 17 kDa protein containing 146 amino acids, with a leucine-zipper like motif at the N-terminal and a proline-rich region that similarity to an Src homolog 3 (SH3)-binding domain (Nagasaki et al., 1999). A shorter 165-bp splice variant is predicted to translate into a truncated protein of 44 amino acids that contains only the leucine-zipper region of wide type protein (Duzakale et al. 2014). |
| Expression | LDOC1 is expressed in a wide variety of normal tissues including heart, brain, lung, skeletal muscles, kidney, pancreas, spleen, thymus, prostate, testis, ovary, stomach, small intestine, colon, adrenal medulla, thyroid, adrenal cortex, thymus (Nagasaki et al., 1999). Down-regulation of LDOC1 have been reported in various kinds of human cancer tissues, including oral cancer (Lee et al., 2013), hepatocellular carcinoma (Riordan and Dupuy, 2013), Chronic lymphocytic leukemia (Duzakale et al., 2014), prostate cancer (Camões et al., 2012), as well as in a variety of human cancer cell lines, including pancreatic cancer cell line, gastric cancer cell lines, some breast cancer cell lines (Nagasaki et al., 1999), ovarian cancer cell lines (Buchholtz et al., 2014), cervical cancer cell lines (Buchholtz et al., 2013) and oral cancer cell lines (Lee et al., 2013). Epigenetic silencing by promoter hypermethylation was shown to be an important cause of LDOC1 down-regulation in oral cancer (Lee et al., 2013), cervical cancer (Buchholtz et al., 2013), and ovarian cancer cells (Buchholtz et al., 2014). |
| Localisation | LDOC1 localizes predominantly in the nucleus (Nagasaki et al., 1999). It may also be retained in cytoplasm through interaction with WAVE3 (Mizutani et al., 2005). |
| Function | Most reports demonstrated that the biological function of LDOC1 is closely related to modulation of apoptosis. Forced expression of LDOC1 induced apoptosis in Jurkat lymphoma cells, K562 leukemia cells (Inoue et al., 2015), Hela cervical cancer cells (Buchholtz et al., 2013) and oral cancer cells (Lee et al., 2013). Expression of LDOC1 also enhanced TNF-? or phorbol 12-myristate 13-acetate (PMA)-induced anti-proliferative effects in pancreatic cancer cells (Nagasaki et al., 2003). A hematopoietic transcriptional factor (MZF-1) important in regulating myeloid cell differentiation and proliferation may interact with LDOC1 and enhance it apoptosis-inducing function in K562 leukemia cells (Inoue et al., 2015). LDOC1 also induced apoptosis and inhibited degradation of p53, resulting in p53 accumulation in MDCK cells. WAVE3 could interact with LDOC1 with its C-terminal verprolin homolog domain and act as a negative regulator of LDOC1. Forced expression of WAVE3 retained LDOC1 in cytoplasm and attenuated the apoptosis-inducing effect of LDOC1 (Mizutani et al., 2005). Expression of LDOC1 also significantly inhibited the NF-?B reporter activity in LDOC1-negative BxPC-3 pancreatic cancer cells (Nagasaki et al., 2003) and suppressed TNF-? induced activation of NF-?B (Lee et al., 2013). LDOC1 may also interact with CCAAT-enhancer binding protein-? (C/EBP?) (Chih et al., 2004). However, in human intrahepatic biliary epithelial cells, over expression LDOC1 increased the expression of NF-?B (p65), promoted IL-2 and TNF-? secretion and inhibited apoptosis (Song et al., 2013). LDOC1 has recently been reported as a eutherian-specific acquired gene that regulates placental endocrine function (Naruse et al., 2014). |
| Homology | HomoloGene:32153 |
| Note | |
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| Entity | Chronic lymphocytic leukemia |
| Prognosis | Expression of LDOC1 mRNA correlated with prognostic cytogenetic markers of chronic lymphocytic leukemia patients. In primary patients, LDOC1 mRNA-positive group of patients had significantly poorer overall survival compared to LDOC1 mRNA-negative group of patients (Duzakale et al., 2014). |
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| Entity | Lymphoma |
| Oncogenesis | Forced expression of LDOC1 induced apoptosis in Jurkat lymphoma cell lines (Inoue et al., 2015). |
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| Entity | Leukemia |
| Oncogenesis | Forced expression of LDOC1 induced apoptosis in K562 leukemia cell lines (Inoue et al., 2015). |
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| Entity | Ovarian cancer |
| Cytogenetics | No gene deletion was detected in the 7 ovarian cancer cell lines. |
| Oncogenesis | Three of the 7 ovarian cancer cell lines showed complete loss of LDOC1 transcription, which may due to hypermethylation and inactivation of LDOC1 promoter. Treatment of de-methylation agent (5-aza-2'-deoxycytidine) on ovarian cancer cells induced transcriptional reactivation of LDOC1 gene (Buchholtz et al., 2014). |
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| Entity | Cervical cancer |
| Cytogenetics | No gene deletion was detected in the 6 cervical cancer cell lines. |
| Oncogenesis | LDOC1 was silenced in 4 of the 6 cervical cancer cell lines. An association of promoter hypermethylation and gene silencing was noted. Reactivation of LDOC1 gene was noted in Me180 and SiHa cervical cancer cell lines by demethylation agent treatment (5-aza-2'-deoxycytidine). Re-expression of LDOC1induced apoptosis-like cell death in Hela cervical cancer cells (Buchholtz et al., 2013). |
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| Entity | Oral cancer |
| Oncogenesis | Hypermethylation and down-regulation of LDOC1 were consistently noted in oral cancer samples and oral cancer cell lines. Reactivation of LDOC1 gene was noted in oral cancer cells by demethylation agent treatment (5-aza-2'-deoxycytidine). Re-expression of LDOC1suppressed TNF-? induced activation of NF-?B and suppressed the colony forming and in vivo tumorigenic abilities of oral cancer cells. Epigenetic silencing of LDOC1 may contribute to alcohol, betel quid and smoking-associated oral carcinogenesis (Lee et al., 2013). |
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| Entity | Prostate cancer |
| Oncogenesis | LDOC1 was one of the two transcriptional units (LDOC1, HPANXC) mapped in a critical region of HPCX locus linked to prostate cancer susceptibility in Finland (Baffoe-Bonnie et al., 2005). In addition, compared to non-malignant prostate tissue, LDOC1 was under-expressed (1.8 fold decrease) in prostate cancer tissues, although no methylation of LDOC1 promoter was noted in prostate tumor samples (Camões et al., 2012). |
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| Entity | Hepato cellular carcinoma |
| Oncogenesis | LDOC1 was downregulated in 60% (29/48) of hepatic cellular carcinoma samples compared to adjacent non-tumor liver tissues (Riordan and Dupuy, 2013). |
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| Entity | Pancreatic cancer |
| Oncogenesis | Down-regulation of LDOC1 was noted in 8 of 9 pancreatic cancer cell lines except CAPAN2 cell line (Nagasaki et al., 1999). LDOC1 was expressed in normal pancreatic tissue (Nagasaki et al., 2003). Expression of LDOC1 significantly inhibited the NF-?B reporter activity but does not affect p53, AP1 and CRE-dependent reporter gene expression in LDOC1-negative BxPC-3 pancreatic cancer cell line. LDOC1 also enhanced TNF-? or phorbol 12-myristate 13-acetate (PMA)-induced anti-proliferative effects in pancreatic cancer cells (Nagasaki et al., 2003). |
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| Entity | Gastric cancer |
| Oncogenesis | Using northern blot, down-regulation of LDOC1 was noted in 6 (100%) of 6 gastric cancer cell lines. LDOC1 was normally expressed in stomach tissue (Nagasaki et al., 1999). |
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| Entity | Lung cancer |
| Oncogenesis | LDOC1 was differentially expressed in MASPIN-overexpression lung carcinoma cells (LC5) compared to MASPIN-knockdown LC5 cells (Liu et al., 2012). |
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| Entity | Esophageal cancer |
| Oncogenesis | LDOC1 was down-regulated in a radio-sensitive esophageal cancer cell line (TE-11) compared to other relative radio-resistant esophageal cancer cell lines (Ogawa et al., 2008). |
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| Entity | Cutaneous malignant melanoma |
| Oncogenesis | LDOC1 was downregulated in peripheral blood leukocytes from a cutaneous malignant melanoma patient with multiple in-transient metastases, compared to 3 normal controls (Salemi et al., 2010). |
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| Entity | Hypertension |
| Note | LDOC1 gene was consistently influential in a three-endophenotype model for Taiwanese hypertensive males (Lynn et al., 2009). |
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| Entity | Premature ovarian failure/insufficiency (POF/POI) |
| Note | Array comparative genomic hybridization identified a cryptic deletion region of Xq27.2 containing LDOC1 and SPANX genes in a 23-year old woman with premature ovarian failure/insufficiency (Vitek et al., 2012). |
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| Entity | Down's syndrome |
| Note | Gene expression of LDOC1 was increased in peripheral blood leukocytes from 15 (75%) of 20 patients Down's syndrome, as compared to that of 20 age-, sex-matched normal controls (Salemi et al., 2012). |
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| Entity | Biliary atresia |
| Note | Over expression LDOC1 in human intrahepatic biliary epithelial cells increased the expression of NF-?B (p65), promoted IL-2 and TNF-? secretion and inhibited apoptosis of human intrahepatic biliary epithelial cells, which may induce intrahepatic biliary epithelial cell hyperplasia and trigger biliary atresia, bile duct stenosis and hepatic fibrosis (Song et al., 2013). |
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| A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region |
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| Hum Genet 2005 Aug;117(4):307-16 |
| PMID 15906096 |
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| Epigenetic silencing of the LDOC1 tumor suppressor gene in ovarian cancer cells |
| Buchholtz ML, Brüning A, Mylonas I, Jückstock J |
| Arch Gynecol Obstet 2014 Jul;290(1):149-54 |
| PMID 24554348 |
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| Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's sarcoma and prostate carcinoma |
| Camões MJ, Paulo P, Ribeiro FR, Barros-Silva JD, Almeida M, Costa VL, Cerveira N, Skotheim RI, Lothe RA, Henrique R, Jerónimo C, Teixeira MR |
| PLoS One 2012;7(11):e49819 |
| PMID 23185447 |
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| Protein partners of C/EBPepsilon |
| Chih DY, Park DJ, Gross M, Idos G, Vuong PT, Hirama T, Chumakov AM, Said J, Koeffler HP |
| Exp Hematol 2004 Dec;32(12):1173-81 |
| PMID 15588942 |
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| LDOC1 mRNA is differentially expressed in chronic lymphocytic leukemia and predicts overall survival in untreated patients |
| Duzkale H, Schweighofer CD, Coombes KR, Barron LL, Ferrajoli A, O'Brien S, Wierda WG, Pfeifer J, Majewski T, Czerniak BA, Jorgensen JL, Medeiros LJ, Freireich EJ, Keating MJ, Abruzzo LV |
| Blood 2011 Apr 14;117(15):4076-84 |
| PMID 21310924 |
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| LDOC1, a novel MZF-1-interacting protein, induces apoptosis |
| Inoue M, Takahashi K, Niide O, Shibata M, Fukuzawa M, Ra C |
| FEBS Lett 2005 Jan 31;579(3):604-8 |
| PMID 15670815 |
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| Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma |
| Lee CH, Wong TS, Chan JY, Lu SC, Lin P, Cheng AJ, Chen YJ, Chang JS, Hsiao SH, Leu YW, Li CI, Hsiao JR, Chang JY |
| J Pathol 2013 Jul;230(3):298-309 |
| PMID 23362108 |
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| Comparative proteomic analysis of the function and network mechanisms of MASPIN in human lung cells |
| Liu Y, Geng Y, Li K, Wang F, Zhou H, Wang W, Hou J, Liu W |
| Exp Ther Med 2012 Mar;3(3):470-474 |
| PMID 22969913 |
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| A neural network model for constructing endophenotypes of common complex diseases: an application to male young-onset hypertension microarray data |
| Lynn KS, Li LL, Lin YJ, Wang CH, Sheng SH, Lin JH, Liao W, Hsu WL, Pan WH |
| Bioinformatics 2009 Apr 15;25(8):981-8 |
| PMID 19237446 |
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| WAVE3 functions as a negative regulator of LDOC1 |
| Mizutani K, Koike D, Suetsugu S, Takenawa T |
| J Biochem 2005 Nov;138(5):639-46 |
| PMID 16272576 |
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| Leucine-zipper protein, LDOC1, inhibits NF-kappaB activation and sensitizes pancreatic cancer cells to apoptosis |
| Nagasaki K, Schem C, von Kaisenberg C, Biallek M, Rösel F, Jonat W, Maass N |
| Int J Cancer 2003 Jul 1;105(4):454-8 |
| PMID 12712434 |
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| Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition |
| Naruse M, Ono R, Irie M, Nakamura K, Furuse T, Hino T, Oda K, Kashimura M, Yamada I, Wakana S, Yokoyama M, Ishino F, Kaneko-Ishino T |
| Development 2014 Dec;141(24):4763-71 |
| PMID 25468940 |
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| Identification of candidate genes involved in the radiosensitivity of esophageal cancer cells by microarray analysis |
| Ogawa R, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Mori Y, Mori R, Tomoda K, Katada T, Harada K, Fujii Y |
| Dis Esophagus 2008;21(4):288-97 |
| PMID 18477249 |
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| Domesticated transposable element gene products in human cancer |
| Riordan JD, Dupuy AJ |
| Mob Genet Elements 2013 Sep 1;3(5):e26693 |
| PMID 24251072 |
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| Expression of LDOC1 mRNA in leucocytes of patients with Down's syndrome |
| Salemi M, Barone C, Romano C, Ridolfo F, Salluzzo R, Scillato F, Scavuzzo C, Caraci F, Calogero AE, Romano C, Bosco P |
| J Genet 2012;91(1):95-8 |
| PMID 22546831 |
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| Two proapoptotic genes are downregulated in a patient with melanoma and repeated in-transit metastases |
| Salemi M, Giuffrida D, Soma PF, Giuffrida MC, Galia A, Calogero AE |
| Am J Dermatopathol 2012 Jun;34(4):454-5 |
| PMID 21986234 |
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| Overexpression of LDOC1 in human biliary epithelial cells inhibits apoptosis through NF-B signaling |
| Song Z, Dong R, Zhao R, Zheng S |
| J Pediatr Gastroenterol Nutr 2013 Dec;57(6):713-7 |
| PMID 23942005 |
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| Xq;autosome translocation in POF: Xq27 |
| Vitek WS, Pagidas K, Gu G, Pepperell JR, Simpson JL, Tantravahi U, Plante BJ |
| 2 deletion resulting in haploinsufficiency for SPANX J Assist Reprod Genet |
| PMID 22071885 |
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