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LIM-domain-only proteins in cancer

Key Points

  • All members of the human LIM-domain-only (LMO) family of proteins, LMO1–4, are implicated in the onset or the progression of cancers. In particular, LMO1 and LMO2 are linked to the onset of T cell leukaemia; overexpression of LMO4 is a marker of poor prognosis in breast cancer; and LMO1 and LMO3 are associated with neuroblastoma.

  • The overexpression of LMO2 in T cells is caused by chromosomal translocations (in which T cell receptor genes are inserted upstream of LMO2), chromosomal deletions, insertional mutagenesis during gene therapy trials for SCID-X1, and the upregulation of promoters though transcription factors such as FLI1, ERG and LMO2 itself.

  • LMO2-induced T cell leukaemias have a long latency period. The overexpression of LMO2 results in the upregulation of haematopoietic stem cell genes and the downregulation of T cell differentiation genes, which causes developing thymocytes to stall at the DN3 stage and to undergo self-renewal. The self-renewing cells can accumulate additional mutations (such as activating mutations of NOTCH1) that trigger overt leukaemia.

  • LMO2 seems to function primarily through forming transcription factor complexes with TAL1 or LYL1, GATA proteins, LDB1, and E12 or E47 to regulate gene expression. Other LMO proteins may function in the same way, but apart from LMO1 (which can take the place of LMO2 in haematopoietic transcriptional complexes) their protein partners are less well characterized.

  • LMO4 seems to regulate progression through the cell cycle in breast cancer cell lines, and can act at several different stages of the cell cycle, probably either by affecting transcriptional programmes of proteins that directly control cell cycle progression, or through interaction with such proteins.

  • The overexpression of LMO proteins has been identified in many different types of cancers. In some cases this overexpression can have a protective effect, in other cases the LMO proteins actively promote cancer, but in many other cases a causative or protective role has yet to be determined. In cancers in which LMO proteins are oncogenic, such as LMO2-induced T cell leukaemias, inhibitors of the LMO protein may be of therapeutic value.

Abstract

LIM-domain proteins are a large family of proteins that are emerging as key molecules in a wide variety of human cancers. In particular, all members of the human LIM-domain-only (LMO) proteins, LMO1–4, which are required for many developmental processes, are implicated in the onset or the progression of several cancers, including T cell leukaemia, breast cancer and neuroblastoma. These small proteins contain two protein-interacting LIM domains but little additional sequence, and they seem to function by nucleating the formation of new transcriptional complexes and/or by disrupting existing transcriptional complexes to modulate gene expression programmes. Through these activities, the LMO proteins have important cellular roles in processes that are relevant to cancer such as self-renewal, cell cycle regulation and metastasis. These functions highlight the therapeutic potential of targeting these proteins in cancer.

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Figure 1: Chromosomal aberrations in LMO2-associated T-ALLs.
Figure 2: Induction of thymocyte self-renewal by LMO2.
Figure 3: Multiple roles of LMO4 in cell cycle regulation.

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Acknowledgements

J.M.M. is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia. K.L. and S.J. are supported by Australian Postgraduate Awards. D.J.C. is a recipient of a Charles and Sylvia Viertel Foundation Senior Medical Research Fellowship. This work was supported by grants from the Australian Research Council and NHMRC.

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Correspondence to Jacqueline M. Matthews.

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Senior Research Fellowship from the National Health and Medical Research Council of Australia to J.M.M., Australian Postgraduate Awards to K.L. and S.J. Senior clinical research fellowship from the Charles and Sylvia Viertel Charitable Foundation to D.J.C. Grants from the NHMRC and Australian Research Council for research on LMO proteins to J.M.M. and D.J.C.

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Glossary

Zinc finger

A small (<100-residue) protein domain that coordinates one or more structurally essential zinc ions.

Auto-antigen

A tumour-derived protein that evokes an immune response. These proteins and/or their associated antibodies are potential biomarkers for the early detection of disease.

Double-negative thymocytes

Pre-T cells that lack expression of both cluster of differentiation (CD) receptors CD4 and CD8.

DN3 cells

Pre-T cells in which T cell receptor (TCR) gene rearrangement occurs. These cells are CD4- and CD8-negative, and CD24-, CD25- and THY1-positive, have low levels of KIT and CD44, and express CD27 once activated by TCR-dependent selection.

Stemness

The essential characteristics of a stem cell (such as self-renewal and pluripotency) that distinguish it from ordinary cells.

GATA proteins

Vertebrates have six GATA family proteins, GATA1–6. In general, GATA1–3 are associated with haematopoiesis, and GATA4–6 with heart, smooth muscle and endoderm development.

E47

A bHLH protein isoform. E12 and E47 are collectively termed E2α proteins. They are both encoded by the transcription factor 3 gene (TCF3; also known as E2A), and the isoforms are generated through alterative splicing.

E12

A bHLH protein isoform. E12 and E47 are collectively termed E2α proteins. They are both encoded by the transcription factor 3 gene (TCF3; also known as E2A), and the isoforms are generated through alterative splicing.

DN4 cells

Final stage of double-negative cells. These cells are CD4- and CD8-negative, and CD24-, CD27- and THY1-positive, and have low levels of expression of KIT, CD44 and CD25.

Basal-like breast cancers

Breast cancers of poor prognosis that express epidermal growth factor receptor (EGFR) and/or cytokeratin 5 (CK5) and CK6. They are typically triple negative; that is, lacking expression of the oestrogen receptor (ER), progesterone receptor (PR) and ERBB2.

Intrabody

An antibody that works within the cell to bind to an intracellular target.

Aptamers

Peptide or oligonucleotide molecules that bind to a specific site on a target molecule.

C-X-X-C motif

Also known as a rubredoxin or zinc knuckle. A half metal-coordinating motif in which C is cysteine and X is any other amino acid. Two C-X-X-C (C-X-X-C-like) motifs coordinate each zinc ion in LIM domains.

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Matthews, J., Lester, K., Joseph, S. et al. LIM-domain-only proteins in cancer. Nat Rev Cancer 13, 111–122 (2013). https://doi.org/10.1038/nrc3418

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