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HGNC Approved Gene Symbol: LASP1
Cytogenetic location: 17q12 Genomic coordinates (GRCh38) : 17:38,870,058-38,921,770 (from NCBI)
By differential screening of cDNAs from breast cancer-derived metastatic axillary lymph nodes, Tomasetto et al. (1995) identified TRAF4 (602464) and 3 other novel genes that are overexpressed in breast cancer. They designated one of these genes, which mapped to chromosome 17q, MLN50. In breast cancer cell lines, overexpression of the 4-kb MLN50 mRNA was correlated with amplification of the gene and with amplification and overexpression of ERBB2 (164870), which maps to the same region. The authors suggested that the 2 genes belong to the same amplicon. Amplification of chromosomal region 17q11-q21 is one of the most common events occurring in human breast cancers (Tomasetto et al., 1995).
Tomasetto et al. (1995) reported that the predicted 261-amino acid MLN50 protein contains an N-terminal LIM domain and a C-terminal SH3 domain. They renamed the protein LASP1, for 'LIM and SH3 protein.' Northern blot analysis revealed that LASP1 mRNA was expressed at a basal level in all normal tissues examined and overexpressed in 8% of primary breast cancers. In most of these cancers, LASP1 and ERBB2 were simultaneously overexpressed.
Schreiber et al. (1998) isolated cDNAs encoding mouse Lasp1. They determined that both human and mouse LASP1 contain an actin-binding domain.
Tomasetto et al. (1995) mapped the LASP1 gene to chromosome 17q11-q21.3 by radioactive in situ hybridization.
Using in situ hybridization, Schreiber et al. (1998) mapped the mouse Lasp1 gene to the 11C-11D region of chromosome 11.
By yeast 2-hybrid, truncation, and pull-down analyses, Li et al. (2004) found that an N-terminal motif of zyxin (ZYX; 602002) interacted with the C-terminal SH3 domains of LIM-nebulette (605491), nebulin (NEB; 161650), and LASP1, but not with the SH3 domains of other proteins examined. Zyxin, LIM-nebulette, and LASP1 colocalized at focal adhesions in transfected HeLa and HT1080 cells.
Traenka et al. (2010) stated that LASP1 is frequently overexpressed in metastatic human breast cancer and ovarian cancer. Using expression profiling, quantitative real-time PCR, and immunohistochemical analysis, they found that LASP1 mRNA and protein were overexpressed in medulloblastomas and that LASP1 overexpression correlated with chromosome 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was strong in 2 of 5 recurrent medulloblastomas in which no LASP1 expression was detected in patient-matched primary tumors. In 2 adherent medulloblastoma cell lines, LASP1 expression was associated with focal adhesion contacts, with intense colocalization with filamentous actin. In an adherent/suspension medulloblastoma cell line with isochromosome 17q and abnormal neurofilament expression, LASP1 localization with filamentous actin was less definite but present at the leading edges of cells. Knockdown of LASP1 expression in all 3 medulloblastoma cell lines reduced cell proliferation and migratory potential and enhanced cell adhesion. Differential display analysis showed that knockdown of LASP1 resulted in upregulation of genes involved in cell adhesion and downregulation of genes involved in invasion and migration.
LASP1/MLL Fusion Gene
The MLL gene (159555), located on chromosome 11q23, is frequently rearranged in acute leukemia. Strehl et al. (2003) identified a new MLL fusion partner on chromosome 17q in the case of an infant with AML-M4 (see 601626) and a t(11;17)(q23;q21) translocation. FISH and RT-PCR analyses indicated a rearrangement of the MLL gene, but no fusion with previously identified MLL fusion partners at 17q, such as AF17 (600328) or MSF (604061). RACE revealed an in-frame fusion of MLL to LASP1. The authors stated that retroviral transduction of myeloid progenitors demonstrated that LASP1/MLL was the fourth known fusion of MLL with a cytoplasmic protein that has no in vitro transformation capability, the others being GRAF (605370), FBP17 (606193), and ABI1 (603050).
Li, B., Zhuang, L., Trueb, B. Zyxin interacts with the SH3 domains of the cytoskeletal proteins LIM-nebulette and Lasp-1. J. Biol. Chem. 279: 20401-20410, 2004. [PubMed: 15004028] [Full Text: https://doi.org/10.1074/jbc.M310304200]
Schreiber, V., Masson, R., Linares, J. L., Mattei, M. G., Tomasetto, C., Rio, M. C. Chromosomal assignment and expression pattern of the murine Lasp-1 gene. Gene 207: 171-175, 1998. [PubMed: 9511759] [Full Text: https://doi.org/10.1016/s0378-1119(97)00622-7]
Strehl, S., Borkhardt, A., Slany, R., Fuchs, U. E., Konig, M., Haas, O. A. The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21). Oncogene 22: 157-160, 2003. [PubMed: 12527918] [Full Text: https://doi.org/10.1038/sj.onc.1206042]
Tomasetto, C., Moog-Lutz, C., Regnier, C. H., Schreiber, V., Basset, P., Rio, M.-C. Lasp-1 (MLN 50) defines a new LIM protein subfamily characterized by the association of LIM and SH3 domains. FEBS Lett. 373: 245-249, 1995. [PubMed: 7589475] [Full Text: https://doi.org/10.1016/0014-5793(95)01040-l]
Tomasetto, C., Regnier, C., Moog-Lutz, C., Mattei, M. G., Chenard, M. P., Lidereau, R., Basset, P., Rio, M. C. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17. Genomics 28: 367-376, 1995. [PubMed: 7490069] [Full Text: https://doi.org/10.1006/geno.1995.1163]
Traenka, C., Remke, M., Korshunov, A., Bender, S., Hielscher, T., Northcott, P. A., Witt, H., Ryzhova, M., Felsberg, J., Benner, A., Riester, S., Scheurlen, W., Grunewald, T. G. P., von Deimling, A., Kulozik, A. E., Reifenberger, G., Taylor, M. D., Lichter, P., Butt, E., Pfister, S. M. Role of LIM and SH3 protein 1 (LASP1) in the metastatic dissemination of medulloblastoma. Cancer Res. 70: 8003-8014, 2010. [PubMed: 20924110] [Full Text: https://doi.org/10.1158/0008-5472.CAN-10-0592]