Disease relevance of l(2)gl

• Analysis of metastasis patterns of the lines containing P element insertions and lacking wild-type l(2)gl expression identified three homozygous mutations that dramatically alter tumorigenesis and/or metastasis [1].
• Recessive mutations at the lethal(2)giant larvae (l(2)gl) locus of Drosophila melanogaster cause a complex syndrome, which has as its most striking features the development of malignant neuroblastomas in the larval brain and tumors of the imaginal discs [2].
• Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer [3].
• While mutations in both lgl and brat cause neoplastic brain tumors, our results reveal that metastatic cells arising from these tumors have quite different properties [4].

Psychiatry related information on l(2)gl

• These phenotypes are accompanied by an arrest of the cell shape changes normally occurring in lateral epidermis and in epithelial midgut cells. l(2)gl activity is also necessary for larval fife and the critical period falls within the third instar larval stage [5].

High impact information on l(2)gl

• Similar defects are seen in lethal giant larvae (lgl) mutants where Brat and Prospero are not asymmetric [6].
• We have previously cloned lethal(2)giant larvae, a tumor-suppressor gene of Drosophila that normally controls cell proliferation and/or differentiation in the optic centers of the brain and the imaginal discs [7].
• Basal protein targeting requires microfilament and myosin function, yet the lgl phenotype is strongly suppressed by reducing levels of myosin II [8].
• The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts [8].
• Here we identify several candidate Hox gene targets, including a mouse homologue of the Drosophila tumour-suppressor gene l(2)gl, by immunopurification of DNA sequences bound to a Hox protein in native chromatin [9].

Biological context of l(2)gl

• Random homozygous P element insertions were screened for the ability to modulate the l(2)gl phenotype [1].
• Phospho-Mad and the downstream target gene vestigial were elevated in l(2)gl tumors, thus linking Drosophila neoplasia to the Dpp (TGF-beta-like) signal pathway [1].
• The transgene can fully rescue the development of l(2)gl flies raised at 22 degrees C but causes drastic effects on their development at 29 degrees C confirming the temperature sensitivity of the phenylalanine substitution at position 311 [10].
• These findings confirm that p127 is a component of a cytoskeletal network including myosin and suggest that the neoplastic transformation resulting from l(2)gl gene inactivation may be caused by the partial disruption of this network [11].
• The Drosophila tumor suppressor protein lethal (2) giant larvae (l(2)gl) is involved in asymmetric cell division during development and epithelial cell polarity through interaction with the aPKC.Par-6 complex [12].

Anatomical context of l(2)gl

• Our investigations into the l(2)gl function have revealed that the gene product, or p127 protein, acts as a cytoskeletal protein distributed in both the cytoplasm and on the inner face of lateral cell membranes in a number of tissues throughout development [11].
• Inactivation of the Drosophila lethal(2)giant larvae (l(2)gl) gene causes malignant tumors in the brain and the imaginal discs and produces developmental abnormalities in other tissues, including the germline, the ring gland and the salivary glands [11].
• Stoichiometric levels of zipper and l(2)gl are required for proper segregation of cellular determinants during neuroblast stem cell division [13].
• Moreover, we show that crb and lgl cooperate in zonula adherens formation early in development [14].
• These data indicate that during oogenesis p127 plays a critical function at the onset of vitellogenesis and regulates growth of the oocyte, follicle cell migration over the oocyte and their organization in a palisadic epithelium, as well as viability of the germline cells [10].

Associations of l(2)gl with chemical compounds

• This dissociation can be inhibited by staurosporine and a 26mer peptide covering amino acid positions 651 to 676 of p127 and containing five serine residues which are evolutionarily conserved from Drosophila to humans [15].

Physical interactions of l(2)gl

• Further blot overlay assay showed that p127 can directly interact with nonmuscle myosin II [11].
• In Drosophila neuroblasts, the apical DmPar6/DaPKC complex inhibits Lethal giant larvae (Lgl) to promote the basal localization of fate determinants [16].

Regulatory relationships of l(2)gl

• Transcription of Dfos is stimulated by brain tumours of l(2)gl-deficient larvae of Drosophila melanogaster [17].

Other interactions of l(2)gl

• The Drosophila lethal(2)giant larvae tumor suppressor protein forms homo-oligomers and is associated with nonmuscle myosin II heavy chain [11].
• The activation of the Dpp pathway in l(2)gl tumors occurred only in the presence of Sema-5c [1].
• We show that the tumor suppressors lethal giant larvae (lgl) and discs-large (dlg) have identical effects on all three epithelia, and that scrib also acts as a tumor suppressor [18].
• The Drosophila tumor suppressor gene lethal(2)giant larvae is required for the emission of the Decapentaplegic signal [19].
• They also suggest that in the absence of lgl pathway activity, the crb pathway is not required to maintain epithelial polarity [14].

Analytical, diagnostic and therapeutic context of l(2)gl

• Deletion of Drosophila lethal giant larvae (l(2)gl) leads to highly invasive and widely metastatic tumors on transplantation into adult flies [1].
• Having identified the nucleotide change occurring in the l(2)gl(ts3) sequence, we produced by site-directed mutagenesis the identical change leading to the substitution of a serine by a phenylalanine at position 311 of p127l(2)gl and introduced the modified l(2)glF311 gene into l(2)gl flies [10].
• Using gel filtration and immunoaffinity chromatography we found that p127 is consistently recovered as high molecular weight complexes that contain predominantly p127 and at least ten additional proteins [11].
• We have analyzed the cellular localization of transcripts and a 130-kDa protein encoded by the l(2)gl gene, using in situ hybridization and immunofluorescence techniques [20].
• We have cloned a rat homologue of the Drosophila recessive oncogene lethal (2) giant larvae from rat brain by RT-PCR using primers prepared from sequences conserved amongst lgl family genes [21].

References