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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review LPP (lipoma preferred partner) Marleen M Petit Laboratory for Molecular Oncology, Department of Human Genetics, University of Leuven (K.U.Leuven) & VIB, Herestraat 49, B-3000 Leuven, Belgium (MMP) Published in Atlas Database: May 2004 Online updated version: http://AtlasGeneticsOncology.org/Genes/LPPID72.html DOI: 10.4267/2042/38093 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity DNA/RNA HGNC (Hugo): LPP Location: 3q27-q28 Description At least 11 exons; predicted start codon in exon 3, stop codon in exon 11; the protein coding region is covered by the overlapping "CEPH Mark 1" YAC clones 135H6 and 192B10 (start codon in 135H6, stop codon in 192B10) and is dispersed over at least 400 kb genomic DNA; the LIM domains are encoded by separate exons: LIM 1 is encoded by exon 8, LIM 2 by exon 9, and LIM 3 by exon 10 and part of exon 11. Transcription mRNA: ubiquitously: > 10 kb; testis: additional transcripts of 1.8 kb and 1.25 kb. Pseudogene No pseudogenes. Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(3) 204 LPP (lipoma preferred partner) Petit MM Prognosis Can be surgically removed with no recurrence in most cases. Cytogenetics More than 60% of solitary lipomas have an aberrant karyotype; 2/3 of these carry 12q15 rearrangements, most often translocations, affecting the HMGA2 gene; 1/4 of the latter have chromosomal region 3q27-q28 (containing LPP) as 12q15 translocation partner as such creating an HMGA2/LPP fusion gene. Hybrid/Mutated gene HMGA2/LPP hybrid gene containing the first three exons of HMGA2 and exons 8-11 or 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal protein HMGA2/LPP fusion transcripts encode the three DNAbinding domains of HMGA2 followed by two LIM domains (LIM 2 and LIM 3) or a portion of the prolinerich region and all three LIM domains of LPP. Protein Description 612 amino acids; proline-rich region (amino-terminal 2/3 of the protein) followed by three LIM domains (carboxy-terminal 1/3 of the protein). Proline-rich region contains an alfa-actinin binding site, two VASPbinding motifs, and a nuclear export signal. Expression Smooth muscle marker; readily detected on Western blot with an LPP-antibody in all fibroblastic and epithelial cell lines tested to date. Localisation LPP is present in the cytoplasm of cells as well as at sites of cell adhesion such as focal adhesions (attachments sites to the extracellular matrix) and cellcell contacts; LPP also shuttles to the nucleus and its nuclear-cytoplasmic localisation is regulated in part by a nuclear export signal (NES) which is sensitive to the drug leptomycin B. Pulmonary chondroid hamartomas Disease Benign mesenchymal tumors of the lung. Prognosis good Cytogenetics More than 70% of pulmonary chondroid hamartomas have an aberrant karyotype; 70% of these carry 12q15 rearrangements, most often translocations, affecting the HMGA2 gene; 1/8 of the latter have chromosomal region 3q27-q28 (containing LPP) as 12q15 translocation partner as such creating an HMGA2/LPP fusion gene. Hybrid/Mutated gene HMGA2/LPP hybrid gene containing the first three exons of HMGA2 and exons 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal protein HMGA2/LPP fusion transcripts encode the three DNAbinding domains of HMGA2 followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP. Function Because of their structural features (many proteinprotein interaction domains) and their characteristic to shuttle between the nucleus and the cytoplasm, LPP and its family members (see below) have been proposed to be scaffolding proteins involved in signal transduction from sites of cell adhesion to the nucleus; LPP has been shown to harbour transcriptional activation capacity in luciferase reporter assays, suggesting that LPP may be directly involved in the regulation of gene expression; LPP was found to be highly expressed in smooth muscle, and a role for LPP in regulating cell motility was proposed; the precise function of LPP remains to be elucidated. Homology LPP is a member of the zyxin family of proteins, which contains five members: ajuba, LIMD1, LPP, TRIP6 and zyxin. The family hallmark of these proteins are three clustered LIM domains at the carboxy-terminus, which are protein interaction domains. All family members are present at sites of cell adhesion and have the ability to shuttle to the nucleus, and all family members have one or more nuclear export signals. Parosteal lipoma Disease Rare deep-seated benign tumor of adipose tissue comprising less than 0.5% of all lipomas; parosteal lipomas exhibit a contiguous relationship with the periostium; because of their intimate relationship to the bone, they are considered as lipomas of bone. Prognosis Most often asymptomatic; in some cases: loss of motor and/or sensory function as a result of the compression or stretching of a nerve. Mutations Somatic HMGA2/LPP fusion proteins and MLL/LPP fusion proteins (Fig2). Implicated in Solitary lipomas Disease Benign tumors of adipose tissue. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(3) 205 LPP (lipoma preferred partner) Petit MM case reported with rearrangement of LPP t(3;12)(q27;q15). Hybrid/Mutated gene HMGA2/LPP hybrid gene containing the first three exons of HMGA2 and exons 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal protein HMGA2/LPP fusion transcripts encode the three DNAbinding domains of HMGA2 followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP. Cytogenetics One case reported with rearrangement of LPP t(3;12)(q28;q14). Hybrid/Mutated gene HMGA2/LPP hybrid gene containing the first three exons of HMGA2 and exons 9-11 of LPP; under the regulation of the HMGA2 promoter. Abnormal protein HMGA2/LPP fusion transcripts encode the three DNAbinding domains of HMGA2 followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP. AML-M5 Soft tissue chondroma Disease Secondary leukemia following treatment with DNA topoisomerase II inhibitors. Cytogenetics MLL gene on 11q23 frequently involved; one case reported with rearrangement of LPP t(3;11)(q28;q23). Disease Benign tumor of cartilage; rare entity. Cytogenetics Only 31 cases with abnormal karyotypes have been reported (11-2003); 12q15 nonrandomly involved; one Atlas Genet Cytogenet Oncol Haematol. 2004; 8(3) 206 LPP (lipoma preferred partner) Petit MM fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23). Genes Chromosomes Cancer. 2001 Aug;31(4):3829 Hybrid/Mutated gene MLL/LPP hybrid gene containing the first 8 exons of MLL and exons 9-11 of LPP; under the regulation of the MLL promoter. Abnormal protein MLL/LPP fusion transcripts encode the three DNAbinding domains and the methyltransferase-like domain of MLL followed by the two most carboxy-terminal LIM domains (LIM 2 and LIM 3) of LPP. Lemke I, Rogalla P, Bullerdiek J. A novel LPP fusion gene indicates the crucial role of truncated LPP proteins in lipomas and pulmonary chondroid hamartomas. Cytogenet Cell Genet. 2001;95(3-4):153-6 Dahlén A, Mertens F, Rydholm A, Brosjö O, Wejde J, Mandahl N, Panagopoulos I. Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol. 2003 Nov;16(11):1132-40 References Gorenne I, Nakamoto RK, Phelps CP, Beckerle MC, Somlyo AV, Somlyo AP. LPP, a LIM protein highly expressed in smooth muscle. Am J Physiol Cell Physiol. 2003 Sep;285(3):C674-85 Petit MM, Mols R, Schoenmakers EF, Mandahl N, Van de Ven WJ. LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family. Genomics. 1996 Aug 15;36(1):118-29 Li B, Zhuang L, Reinhard M, Trueb B. The lipoma preferred partner LPP interacts with alpha-actinin. J Cell Sci. 2003 Apr 1;116(Pt 7):1359-66 Petit MM, Swarts S, Bridge JA, Van de Ven WJ. Expression of reciprocal fusion transcripts of the HMGIC and LPP genes in parosteal lipoma. Cancer Genet Cytogenet. 1998 Oct 1;106(1):18-23 Nelander S, Mostad P, Lindahl P. Prediction of cell typespecific gene modules: identification and initial characterization of a core set of smooth muscle-specific genes. Genome Res. 2003 Aug;13(8):1838-54 Rogalla P, Kazmierczak B, Meyer-Bolte K, Tran KH, Bullerdiek J. The t(3;12)(q27;q14-q15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype. Genes Chromosomes Cancer. 1998 Jun;22(2):100-4 Petit MM, Meulemans SM, Van de Ven WJ. The focal adhesion and nuclear targeting capacity of the LIM-containing lipomapreferred partner (LPP) protein. J Biol Chem. 2003 Jan 24;278(4):2157-68 Petit MM, Fradelizi J, Golsteyn RM, Ayoubi TA, Menichi B, Louvard D, Van de Ven WJ, Friederich E. LPP, an actin cytoskeleton protein related to zyxin, harbors a nuclear export signal and transcriptional activation capacity. Mol Biol Cell. 2000 Jan;11(1):117-29 This article should be referenced as such: Petit MM. LPP (lipoma preferred partner). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(3):204-207. Dahéron L, Veinstein A, Brizard F, Drabkin H, Lacotte L, Guilhot F, Larsen CJ, Brizard A, Roche J. Human LPP gene is Atlas Genet Cytogenet Oncol Haematol. 2004; 8(3) 207