Identification of the LMO4 gene encoding an interaction partner of the LIM-binding protein LDB1/NLI1: a candidate for displacement by LMO proteins in T cell acute leukaemia

Abstract

The T cell oncogenes LMO1 and LMO2 are activated by distinct chromosomal translocations in childhood T cell acute leukaemias. Transgenic mouse models of this disease demonstrate that enforced expression of Lmo1 and Lmo2 cause T cell leukaemias with long latency and that Lmo2 expression leads to an inhibition of the T cell di erentiation programme, prior to overt disease. These functions appear to be partly mediated by interaction of LMO1 or LMO2 with the LIM-binding protein LDB1/ NLI1. We have now identi®ed a new member of the Lmo family, designated Lmo4, via its interaction with Ldb1. Lmo4 is widely expressed in mouse tissues, including adult thymus (mainly CD4, CD8-double positive T cells) and embryonic thymus (mainly CD4, CD8-double negative T cells). These characteristics imply that Ldb1-Lmo4 interaction may function in the T cell developmental programme and that enforced expression of LMO1 or LMO2 by chromosomal translocations or transgenesis may displace Lmo4 from this complex and thereby in¯uence T cell di erentiation prior to T cell tumour occurrence.

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

“…LMO4 and LDB1 in oral squamous cell carcinoma H Mizunuma et al facilitates the formation of an aberrant multimeric complex (Grütz et al, 1998;Rabbitts, 1998). Although the role in the pathology of carcinomas of epithelial origin is not clear, Visvader et al (2001) recently indicated that LMO4 and LDB1 are required to maintain the undifferentiation state of invasive breast carcinoma cells, and the forced expression of LMO4 inhibits differentiation of mammary epithelial cells.…”

“…Another intriguing possibility comes from a study that GATA zinc-finger proteins interact with the LMO2 -LDB1 complex and specifies a haematopoietic lineage differentiation (Wadman et al, 1997). However, overexpression of LMO2 in T-cell leukaemia results in the formation of a novel aberrant complex that substitutes a GATA protein to the E-box (CANNTG) binding bHLH and inhibits T-cell differentiation (Grütz et al, 1998). The C. elegans homologue of GATA, Elt, is a prerequisite for ectodermal cell differentiation (Gilleard and McGhee, 2001).…”

Expression of an engrailed-LMO4 fusion protein in mammary epithelial cells inhibits mammary gland development in mice

“…LMO4, simultaneously discovered by other laboratories (Grutz et al, 1998;Kenny et al, 1998), is the main LIM domain factor expressed in proliferating epithelial cells of the epidermis and hair follicles (Sugihara et al, 1998). Interestingly, the human LMO4 gene was initially cloned from a breast cancer cDNA library (Racevskis et al, 1999), and subsequent studies showed it to be overexpressed in more than half of all invasive breast carcinomas (Visvader et al, 2001).…”

Expression of LMO4 and outcome in pancreatic ductal adenocarcinoma

“…Several LMO4-interacting proteins have been identified, including the ubiquitous nuclear adaptor protein Lbd1 (Grutz et al, 1998), the transcription factor deformed epidermal autoregulatory factor 1 (Sugihara et al, 1998), the basic helix-loop-helix protein HEN1 (Manetopoulos et al, 2003) and the grainyhead-like epithelial transactivator (Kudryavtseva et al, 2003), as well as the cofactor CtIP and BRCA1.…”