| Written | 2012-06 | Andrea Vecchione, Luca Lavra, Carlo M Croce |
| Department of Molecular Virology, Immunology, Medical Genetics, Comprehensive Cancer Center, Ohio State University, OH, USA (AV, CMC); Division of Pathology, Medical Oncology, Department of Clinical, Molecular Medicine, Faculty of Medicine, Psychology, University Sapienza, Santo Andrea Hospital, Rome, Italy (AV, LL) |
| Identity |
| Alias_names | leucine zipper, putative tumor suppressor 1 |
| Alias_symbol (synonym) | FEZ1 |
| Other alias | F37 |
| HGNC (Hugo) | LZTS1 |
| LocusID (NCBI) | 11178 |
| Atlas_Id | 367 |
| Location | 8p21.3 [Link to chromosome band 8p21] |
| Location_base_pair | Starts at 20246165 and ends at 20255292 bp from pter ( according to hg19-Feb_2009) [Mapping LZTS1.png] |
| Local_order | According to the NCBI map viewer, genes flanking LZTS1 from centromere to telomere are: - CLU (8p21-p12): clusterin - PTK2B (8p21.1): protein tyrosine kinase 2 beta - LPL (8p22): lipoprotein lipase - NAT2 (8p22): N-acetyltransferase 2 (arylamine N-acetyltransferase) - CTSB (8p22): cathepsin B - ANGPT2 (8p23.1): angiopoietin 2. |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| Note | The human LZTS1 gene maps on chromosome 8p22 and encodes a leucin zipper protein with a region homologue to cAMP-responsive transcription factor Atf-5, and with different potential phosphorylation sites. It is ubiquitously expressed in normal human tissues and is implicated in cell cycle control by modulating the activity of the Cdk1/cyclin B1 complex. LZTS1 chromosomal locus is frequently deleted in tumors (Ishii et al., 1999) and LZTS1 gene and protein expression is reduced or lost in different human malignancies. The reintroduction of LZTS1 expression into LZTS1 null cancer cell lines suppresses cell growth at the G2/M phase of the cell cycle and inhibits migration and invasion. In conclusion, LZTS1 loss is involved in the neoplastic transformation of different types of tumors indicating that LZTS1 can be considered an important tumor suppressor gene and a potential diagnostic and therapeutic target (Ishii et al., 2001; Vecchione et al., 2002; Vecchione et al., 2007a). |
| DNA/RNA |
| Note | NC_000008.10: 20103676 - 20112803 bp (Entrez-Gene). |
 | |
| Genomic structure of the human LZTS1 gene. | |
| Description | According to Entrez-Gene, LZTS1 gene extends over 9 kb (9128 bases) and consists of 3 exons. |
| Transcription | mRNA size: 5459 bp (NM_021020.2); open reading frame: 1791 bp (NP_066300.1). LZTS1 mRNA is highly expressed in testis, prostate, spleen, thymus, ovary and brain. It has been detected at lower levels in heart, placenta, small intestine, colon, liver, kidney, skeletal muscle and pancreas. LZTS1 gene is not expressed in primary tumors from breast and prostate and in different cancer cell lines (Ishii et al., 1999). |
| Pseudogene | No LZTS1 pseudogenes have been reported. |
| Protein |
 | |
| Schematic representation of LZTS1 protein. The leucine residues position of leucine-zipper motifs are indicated by the gray bars. | |
| Description | LZTS1 gene encodes a 596-aa protein of 67 kDa. The protein contains two leucine-zipper motifs, multiple potential phosphorylation sites for different kinases (e.g. PKA, CDC2 and PKC) and a domain with 32% identity to the DNA binding domain of the cAMP-responsive transcription factor Atf5. LZTS1 lacks the DNA recognition domain usually found in transcription factors carrying a leucine-zipper motive (Ishii et al., 1999; Ishii et al., 2001; Vecchione et al., 2007b). |
| Expression | LZTS1 is ubiquitously expressed in all normal human tissues. LZTS1 protein expression is lost or reduced in different primary tumors. |
| Localisation | Main sub-cellular localizations: plasma membrane and cytoplasm. Additional localizations: nucleoli (observed in U2-OS cells) and Golgi apparatus (observed in A-431 cells) (Barbe et al., 2008). |
| Function | Cell cycle regulation. It has been demonstrated that Lzts1-/- mouse embryonic fibroblasts (MEF) have a faster M phase, associated with a lower cyclin B1/Cdk1 activity. During prophase the interaction between LZTS1 and Cdc25C, a phosphatase implicated in regulation of Cdk1 activity, allows the expression of high levels of Cdc25C and enhances its activity, resulting in normal progression from prophase to metaphase. In Lzts1 deficient cells during prophase Cdc25C is rapidly ubiquitinated and degraded, thus determining a lower activity of the cyclin B1/Cdk1 complex. This results in a faster cellular progression through prophase and prometaphase and, frequently, in chromosome missegregation (Vecchione et al., 2007b). |
| Homology | The LZTS1 gene is conserved in the organisms listed below: - Pan troglodytes (LZTS1) (Gene ID: 464034) - Macaca mulatta (LZTS1) (Gene ID: 705724) - Mus musculus (Lzts1) (Gene ID: 211134) - Rattus norvegicus (Lzts1) (Gene ID: 266711) - Bos taurus (LZTS1) (Gene ID: 539634) - Equus caballus (LZTS1) (Gene ID: 100053630) - Canis lupus familiaris (LZTS1) (Gene ID: 486136) - Monodelphis domestica (LZTS1) (Gene ID: 100030407) - Ornithorhynchus anatinus (LZTS1) (Gene ID: 100073437) - Gallus gallus (LZTS1) (Gene ID: 431331) - Danio rerio (si:dkey-63d15.13) (Gene ID: 569281). |
| Mutations |
| Note | Sequence analysis of LZTS1 ORF, performed in different type of cancers revealed the presence of the somatic point mutations listed hereinafter (Vecchione et al., 2001; Knowles et al., 2005): - S29P: (TCC->CCC) reported in a primary esophageal tumor - K119E: (AAG->GAG) reported in a primary esophageal tumor - Q501Stop: (CAG->TAG) reported in PC3 (prostate cancer cell line) - H17R: (CAC->CGC) reported in a diffuse-type gastric carcinoma - L113P: (CTA->CCA) reported in a bladder tumor sample - G374S: (GGC->AGC) reported in A1698 (bladder cancer cell line) - L475V: (CTG->GTG) reported in SCaBER (bladder cancer cell line). Internally truncated transcripts described in different cancers (Ishii et al., 1999): A detailed DNA sequence analysis of LZTS1 gene performed in germline DNA extracted from a screening panel of sporadic and hereditary prostate cancers revealed the presence of 24 SNP. The four SNP listed below have a statistically significant association with sporadic prostate cancer (Hawkins et al., 2002): |
| Implicated in |
| Note | |
| Entity | Prostate cancer |
| Note | The DNA sequence analysis of LZTS1 performed on sporadic and hereditary prostate cancer (HPC) samples and unaffected controls revealed the presence of several SNPs associated with prostate cancer (Hawkins et al., 2002). Over-expression of LZTS1 cDNA modulates colony-forming efficiency and proliferation in different prostate cancer cell lines (Cabeza-Arvelaiz et al., 2001). |
| Entity | Ovarian cancer |
| Note | An immunohistochemical analysis of LZTS1 protein expression performed in ovarian carcinomas tissue samples demonstrated that cytoplasmic staining for FEZ1 protein was absent or drastically reduced in 38% of cases (Califano et al., 2010). In addition, homozygous deletions at LZTS1 locus has been detected in advanced ovarian clear cell carcinomas (Kuo et al., 2010). |
| Entity | Oral squamous cell carcinoma |
| Note | Reduced LZTS1 gene expression has been reported in 35% of oral squamous cell carcinoma (SSC) samples and in oral SSC-derived cell lines (Ono et al., 2003). |
| Entity | Uveal melanoma |
| Note | A gene expression profiling performed on 53 primary uveal melanomas by array-based comparative genomic hybridization demonstrated that LZTS1 expression was reduced in rapidly metastasizing and metastatic uveal melanomas but not in slowly metastasizing and non metastasizing uveal melanomas. Moreover overexpression of LZTS1 in metastasizing uveal melanoma-derived cells inhibited their motility and invasion (Onken et al., 2008). |
| Entity | Lung carcinoma |
| Note | The immunohistochemical analysis of LZTS1 expression in 103 primary lung cancer specimens demonstrated absence or strong reduction in respectively in more that 42% of cases. A positive correlation between loss of LZTS1 and tumor grading, and between strong LZTS1 expression and mortality rate reduction was also observed (Nonaka et al., 2005). Moreover reduced LZTS1 expression was also detected in several lung cancer derived cell lines (Toyooka et al., 2002). |
| Entity | Gastric carcinoma |
| Note | The immunohistochemical analysis of LZTS1 expression, performed in 88 gastric cancer specimens demonstrated that it is lost or significantly reduced in more than 44% of cases. In addition, DNA allelotyping analysis at the LZTS1 locus showed LOH and microsatellite instability respectively in 18% and 23,5% of cases (Vecchione et al., 2001). |
| Entity | Breast carcinoma |
| Note | LZTS1 gene expression was reduced in breast primary tumors and breast cancer cell lines. The immunohistochemical analysis of LZTS1 expression demonstrated that LZTS1 was absent or down-regulated in primary breast carcinomas compared with normal breast. Moreover, reduced LZTS1 expression was significantly correlated with high histologic grade, lymph node metastasis, and poor prognosis. In addition, DNA methylation analysis demonstrated that LZTS1 loss of expression in breast tumors is correlated with gene methylation. Moreover, overexpression of LZTS1 in breast cancer cell lines inhibits cell proliferation, migration and invasion, and induces morphological and molecular changes characteristic of mesenchymal-to-epithelial transition (Chen et al., 2009; Wang et al., 2011). |
| Entity | Bladder cancer |
| Note | LZTS1 protein expression is reduced in bladder tumor samples and bladder cancer derived cell lines. Reintroduction of LZTS1 expression in TCC derived cell line inhibited cell growth, altered cell cycle progression and suppressed subcutaneous tumor growth in nude mice. Several LZTS1 somatic point mutations have also been reported in bladder cancers tissues and cell lines (Vecchione et al., 2002; Knowles et al., 2005). Moreover, it has been demonstrated by treating heterozygous and nullizygous Lzts1 mice with a classical bladder carcinogen (N-butyl-N-(4-hydroxybutil) nitrosamine, BBN), that the loss of one or both Lzts1 alleles favored development of bladder cancer. These results demonstrated that LZTS1 could represent an important therapeutic target for bladder tumor treatment. |
| Bibliography |
| Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis. |
| Baffa R, Fassan M, Sevignani C, Vecchione A, Ishii H, Giarnieri E, Iozzo RV, Gomella LG, Croce CM. |
| Carcinogenesis. 2008 Apr;29(4):846-8. Epub 2008 Jan 12. |
| PMID 18192690 |
| Take your "M" time. |
| Baldassarre G, Croce CM, Vecchione A. |
| Cell Cycle. 2007 Sep 1;6(17):2087-90. Epub 2007 Jun 21. |
| PMID 17873519 |
| Toward a confocal subcellular atlas of the human proteome. |
| Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Bjorling E, Asplund A, Ponten F, Brismar H, Uhlen M, Andersson-Svahn H. |
| Mol Cell Proteomics. 2008 Mar;7(3):499-508. Epub 2007 Nov 19. |
| PMID 18029348 |
| Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22. |
| Cabeza-Arvelaiz Y, Sepulveda JL, Lebovitz RM, Thompson TC, Chinault AC. |
| Oncogene. 2001 Jul 12;20(31):4169-79. |
| PMID 11464283 |
| FEZ1/LZTS1 protein expression in ovarian cancer. |
| Califano D, Pignata S, Pisano C, Greggi S, Laurelli G, Losito NS, Ottaiano A, Gallipoli A, Pasquinelli R, De Simone V, Cirombella R, Fusco A, Chiappetta G. |
| J Cell Physiol. 2010 Feb;222(2):382-6. |
| PMID 19885841 |
| Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis. |
| Chen L, Zhu Z, Sun X, Dong XY, Wei J, Gu F, Sun YL, Zhou J, Dong JT, Fu L. |
| Breast Cancer Res Treat. 2009 Aug;116(3):471-8. Epub 2008 Aug 7. |
| PMID 18686028 |
| Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. |
| Hawkins GA, Mychaleckyj JC, Zheng SL, Faith DA, Kelly B, Isaacs SD, Wiley KE, Chang BL, Ewing CM, Bujnovszky P, Bleecker ER, Walsh PC, Meyers DA, Isaacs WB, Xu J. |
| Cancer Genet Cytogenet. 2002 Aug;137(1):1-7. |
| PMID 12377406 |
| The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. |
| Ishii H, Baffa R, Numata SI, Murakumo Y, Rattan S, Inoue H, Mori M, Fidanza V, Alder H, Croce CM. |
| Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3928-33. |
| PMID 10097140 |
| FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis. |
| Ishii H, Vecchione A, Murakumo Y, Baldassarre G, Numata S, Trapasso F, Alder H, Baffa R, Croce CM. |
| Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10374-9. Epub 2001 Aug 14. |
| PMID 11504921 |
| Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer. |
| Knowles MA, Aveyard JS, Taylor CF, Harnden P, Bass S. |
| Cancer Lett. 2005 Jul 8;225(1):121-30. Epub 2004 Dec 10. |
| PMID 15922864 |
| DNA copy numbers profiles in affinity-purified ovarian clear cell carcinoma. |
| Kuo KT, Mao TL, Chen X, Feng Y, Nakayama K, Wang Y, Glas R, Ma MJ, Kurman RJ, Shih IeM, Wang TL. |
| Clin Cancer Res. 2010 Apr 1;16(7):1997-2008. Epub 2010 Mar 16. |
| PMID 20233889 |
| Reduced FEZ1/LZTS1 expression and outcome prediction in lung cancer. |
| Nonaka D, Fabbri A, Roz L, Mariani L, Vecchione A, Moore GW, Tavecchio L, Croce CM, Sozzi G. |
| Cancer Res. 2005 Feb 15;65(4):1207-12. |
| PMID 15735004 |
| A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis. |
| Onken MD, Worley LA, Harbour JW. |
| Clin Cancer Res. 2008 Jun 15;14(12):3737-45. |
| PMID 18559591 |
| Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas. |
| Ono K, Uzawa K, Nakatsuru M, Shiiba M, Mochida Y, Tada A, Bukawa H, Miyakawa A, Yokoe H, Tanzawa H. |
| Int J Oncol. 2003 Aug;23(2):297-302. |
| PMID 12851677 |
| Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures. |
| Toyooka S, Fukuyama Y, Wistuba II, Tockman MS, Minna JD, Gazdar AF. |
| Clin Cancer Res. 2002 Jul;8(7):2292-7. |
| PMID 12114433 |
| Fez1/Lzts1 a new mitotic regulator implicated in cancer development. |
| Vecchione A, Croce CM, Baldassarre G. |
| Cell Div. 2007b Aug 24;2:24. |
| PMID 17718912 |
| Down-regulation of leucine zipper putative tumor suppressor 1 is associated with poor prognosis, increased cell motility and invasion, and epithelial-to-mesenchymal transition characteristics in human breast carcinoma. |
| Wang XX, Zhu Z, Su D, Lei T, Wu X, Fan Y, Li X, Zhao J, Fu L, Dong JT, Fu L. |
| Hum Pathol. 2011 Oct;42(10):1410-9. Epub 2011 Mar 21. |
| PMID 21419475 |
| Citation |
| This paper should be referenced as such : |
| Vecchione, A ; Lavra, L ; Croce, CM |
| LZTS1 (leucine zipper, putative tumor suppressor 1) |
| Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):894-897. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/LZTS1ID367ch8p21.html |
| External links |
| REVIEW articles | automatic search in PubMed |
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| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Nov 13 21:34:53 CET 2019 |
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