The t(11;14)(p15;q11) in a T-cell acute lymphoblastic leukemia cell line activates multiple transcripts, including Ttg-1, a gene encoding a potential zinc finger protein.

Abstract

Interchromosomal translocations within lymphoid neoplasms frequently involve the antigen receptor genes. We cloned the breakpoints of the t(l1;14)(p15;q11) in a CD3-negative T-cell acute lymphoblastic leukemia cell line (RPMI 8402) in order to identify new genes potentially involved in T-cell neoplasia. An extensive comparison of both breakpoints and their germ line counterparts indicated that an inadvertant recombinasemediated break at chromosome segment llplS recombined with the 6 T-cell receptor at 14qll. The derivative 11 breakpoint resembles a coding joint in which llplS rather than a variable region was introduced 5' to a D81D82J81 intermediate rearrangement. Conversely, the derivative 14 breakpoint corresponds to a signal joint between the 5' heptamer-spacer-nonamer recombinational signal of Dr, and an isolated heptamer at llplS.Multiple, apparently distinct transcripts were found flanking both breakpoints of 8402. RNAs of 3.5, 4.4, 1.4, and 8.0 kilobases originating from either side of the derivative 14 breakpoint were highly expressed in 8402 compared with other cells. This suggests that this translocation deregulated multiple genes and provides the opportunity to assess any multifactorial contribution they may have to malignancy. We cloned and sequenced several cDNAs representing the 1.4-kilobase transcript (termed Ttg-1 [T-cell translocation gene 1]) from an 8402 library. The predicted protein of 156 amino acids contained two internal repeats which could potentially form zinc fingers.Chromosomal translocations are frequently found in malignant cells but not in their normal cellular counterparts. Moreover, unique translocations are associated with histologically and phenotypically distinct neoplasms (43,56, 57). Lymphoid malignancies often possess translocations at the chromosomal sites of the antigen receptor genes, immunoglobulin genes in B-cell neoplasms, or T-cell receptor (TCR) genes in T-cell neoplasms (for a review, see reference 31). These genes normally rearrange during development to assemble separate variable (V), joining (J), and, at times, diversity (D) segments into a contiguous V(D)J coding joint. A site-specific recombinase cleaves at conserved heptamerspacer-nonamer signal sequences, which flank the coding regions of these gene segments (33,53), removing the intervening DNA segments and ligating the signal sequences to each other to generate extrachromosomal circles (22,41). These genes prove to be the most frequent sites for illegitimate recombinations with nonhomologous chromosomes in lymphoid neoplasms (31).Genes located at the sites of such translocations appear to directly participate in the development or maintenance of the malignant phenotype (29). Interchromosomal translocations can deregulate these candidate oncogenes by a variety of mechanisms. Transcriptional activation due to the introduction of enhancer elements has been shown for c-myc in a transgenic mouse model (1). Disruption of normal transcription by acquired somatic mutation has been noted for c-myc in the t(8;14)(q...

GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-β-dependent apoptotic signalling

“…As LMO1 is a nuclear protein with no DNA-binding activity, it is considered that it interacts with other molecules through its LIM domains when it acts in transcriptional regulation. Though LMO1 was originally isolated as a candidate oncogene for T-cell acute lymphoblastic leukemia (McGuire et al, 1989;Rabbitts, 1998), our study disclosed a crucial role of LMO1 in gastric epithelium differentiation and it may be also involved in gastric carcinogenesis. Recently, phenotypic discrepancies between two Runx3-KO mice gave rise to some argument about the function of Runx3 in the gastric epithelium (Levanon et al, 2002(Levanon et al, , 2003Li et al, 2002;Bae and Ito, 2003).…”

Zyxin and cCRP: two interactive LIM domain proteins associated with the cytoskeleton.

“…The LIM-bomeodomaln proteins are presumed to function as transcription factors and most have clearly been shown to he required for cell lineage determination and/or pattern formation during embryogenesis. LIM proteins lacking homeodomains or other obvious functional domains have also been identified: CRIP (Birkenmeier and Gordon, 1986), ESP1 (Nalik et al, 1989), hCRP (Liebhaber et al, 1990), and rhombotin (Boehm et al, 1990b(Boehm et al, , 1991aMcGuire et al, 1989). Rhombotin, which is also referred to as Ttg-1, is a nuclear protein (McGuire et al, 1991) that is believed to be a proto-oncogene product (Boehm et al, 1988;Boehm et al, 1990a).…”

Specificity of single LIM motifs in targeting and LIM/LIM interactions in situ.

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