LPP, an actin cytoskeleton protein related to zyxin, harbors a nuclear export signal and transcriptional activation capacity.

The LPP gene is the preferred translocation partner of the HMGIC gene in a subclass of human benign mesenchymal tumors known as lipomas. Here we have characterized the LPP gene product that shares 41% of sequence identity with the focal adhesion protein zyxin. LPP localizes in focal adhesions as well as in cell-to-cell contacts, and it binds VASP, a protein implicated in the control of actin organization. In addition, LPP accumulates in the nucleus of cells upon treatment with leptomycin B, an inhibitor of the export factor CRM1. The nuclear export of LPP depends on an N-terminally located leucine-rich sequence that shares sequence homology with well-defined nuclear export signals. Moreover, LPP displays transcriptional activation capacity, as measured by GAL4-based assays. Altogether, these results show that the LPP protein has multifunctional domains and may serve as a scaffold upon which distinct protein complexes are assembled in the cytoplasm and in the nucleus.

LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes.

A major cytogenetic subgroup among human lipomas is characterized by translocations involving the HMGIC gene at 12q15. In the context of an ongoing research program aiming at the elucidation of the functional consequences of HMGIC translocations in the etiology of lipomas, we have isolated a novel human gene, LHFP (lipoma HMGIC fusion partner), that acts as a translocation partner of HMGIC in a lipoma with t(12;13). The LHFP gene was mapped to the long arm of chromosome 13, a region recurrently targeted by chromosomal aberrations in lipomas. By Northern blot analysis, a transcript of 2. 4 kb was detected in a variety of human tissues. We assembled a cDNA contig containing the entire coding region of LHFP. Nucleotide sequence analysis of the composite LHFP cDNA revealed an open reading frame encoding a protein of 200 amino acids. The predicted human LHFP protein is almost identical to a translated mouse EST that covers almost the entire LHFP coding region. In addition, BLAST searches revealed that the LHFP protein belongs to a new protein family consisting of at least four or five members. In the lipoma studied, the expressed HMGIC/LHFP fusion transcript encodes the three DNA binding domains of HMGIC followed by 69 amino acids encoded by frame-shifted LHFP sequences. LHFP is the second translocation partner of HMGIC identified in lipomas and represents a candidate target gene for lipomas with 13q aberrations.

Expression of reciprocal fusion transcripts of the HMGIC and LPP genes in parosteal lipoma.

Parosteal lipomas are rare benign neoplasms of adipose tissue that exhibit a contiguous relationship with the periosteum. These lipomas of the bone share some histopathologic features with their commonly occurring soft tissue counterparts. The latter are well-characterized cytogenetically, primarily by rearrangements involving chromosome region 12q13-q15. In particular, translocations involving 12q13-q15 are prominent, with chromosomal region 3q27-q28 as the most frequent translocation partner. Recently, we established that the genes HMGIC at 12q15 and LPP at 3q27-28 are affected by the 3;12-translocation and demonstrated that, as a direct result, HMGIC/LPP and LPP/HMGIC fusion transcripts are expressed in soft tissue lipomas. In this study, cytogenetic and molecular analyses revealed similar findings in a parosteal lipoma. Specifically, a t(3;12)(q28;q14) was detected cytogenetically in a parosteal lipoma from a 51-year-old female and subsequently confirmed by FISH utilizing a chromosome 3 breakpoint spanning YAC probe and chromosome 12 breakpoint flanking cosmid probes. RT-PCR analysis showed expression of HMGIC/LPP and LPP/HMGIC fusion transcripts in this parosteal lipoma; nucleotide sequence analysis revealed that these transcripts are identical to those expressed in soft tissue lipomas characterized by a 3;12-translocation. These findings lend further support to a common histopathogenesis between lipomas of soft tissue and parosteal origin.

LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family.

A major cytogenetic subgroup of lipomas is characterized by recurrent chromosome aberrations, mainly translocations, that involve chromosome segment 12q13-q15. Multiple chromosomes have been found as the translocation partners of chromosome 12 but 3q27-q28 is preferentially involved. In previous studies, it has been shown that the high mobility group (HMG) protein gene HMGIC at 12q15 is consistently rearranged as a consequence of these translocations. Here, we report the identification and characterization of the chromosome 3-derived translocation partner gene, which we have designated LPP (lipoma preferred partner gene). Using 3'-RACE analysis of HMGIC fusion transcripts in lipoma cell line Li-501/SV40, ectopic genetic sequences were obtained, which by CASH (chromosome assignment using somatic cell hybrids) and FISH (fluorescence in situ hybridization) analysis were found to originate from chromosome segment 3q27-q28. In Northern blot analysis, an mRNA of over 10 kb was detected by these ectopic sequences in a variety of human tissues but not in brain and peripheral blood leukocytes. Upon partial cDNA cloning, features of the genetic organization of LPP were established. The gene was found to span a genomic region of over 400 kb. Nucleotide sequence analysis of a composite cDNA of LPP revealed an open reading frame of 1836 nucleotides encoding a proline-rich protein containing a leucine-zipper motif in its amino-terminal region and three LIM domains in its carboxy-terminal region. The LPP-encoded protein should be classified as a novel member of the group 3 proteins of the LIM protein gene family. Using reverse transcriptase combined with polymerase chain reactions in the analysis of a number of lipoma cell lines and primary lipomas, it appeared that LPP is frequently rearranged also in cases without a cytogenetically detectable involvement of 3q27-q28. Two alternative HMGIC/LPP hybrid transcripts have been detected; the difference between them is mainly the presence of either two or three LIM domains in the predicted HMGI-C/LPP fusion proteins.