LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at chromosome 3p21.3, binds pRB and represses E2F-driven transcription

Sharp, Tyson V.; Muñoz, F; Bourboulia, Dimitra; Presneau, Nadège; Darai, Eva; Wang, Hsei‐Wei; Cannon, Mark; Butcher, David N.; Nicholson, Andrew G.; Klein, George; Imreh, Stefan; Boshoff, Chris

doi:10.1073/pnas.0407123101

Cited by 78 publications

(125 citation statements)

References 38 publications

(47 reference statements)

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“…In some cases the staining for LIMD1 expression was so dark that many of the nuclei could not be seen. Such staining patterns support previous studies showing LIMD1 family members localising to the cytosol 19,34 and more recently LIMD1 itself localised to the nucleus. 35 In contrast LIMD1 was not present in foam cells or the surrounding stroma of the breast (Fig.…”

Section: Limd1 Expression In Normal Breast Tissuesupporting

confidence: 91%

“…Furthermore, these effects may be in part through the ability of LIMD1 to regulate Snail function through differential subcellular localization and thus, ultimately, ECAD expression as well as the pRb/E2F cell cycle control mechanism. 19 FIGURE 6 -Proposed model for correlation of LIMD1 expression pattern in breast cancer with the indicated variables. Overall TMA staining pattern (top 4 representative panels) have been summarised into 4 distinct pictorial representations: (a) no nuclear/weak cytoplasmic; (b) moderate-heavy nuclear/weak to moderate cytoplasmic; (c) strong nuclear/moderate cytoplasmic and (d) strong nuclear/strong cytoplasmic.…”

Section: Discussionmentioning

confidence: 99%

“…19 LIMD1 blocks tumour growth and is downregulated in all human lung cancer samples tested. 19 These data indicate LIMD1 is a TSG and its loss may promote lung carcinogenesis.Recent findings have demonstrated that LIMD1 and the Ajuba family members are essential components of the Slug/Snail transcriptional repressing complex involved in neural crest development and possible epithelial mesenchymal transition (EMT). [20][21][22] More specifically, LIMD1 and family member Ajuba inhibit Ecadherin (ECAD) transcription via binding to the SNAG domain of Snail and thus act as a co-repressing complex with Snail on the ECAD promoter.…”

mentioning

confidence: 83%

“…37 The equilibrium of which is toward nuclear export thus resulting in most family members including LIMD1 being predominantly localised to the cytoplasm. 19,37,38 In light of the observation of differential staining patterns and intensities for LIMD1 in different breast tumour samples, we examined whether there was a direct correlation between high cytoplasmic levels of LIMD1 and high nuclear levels and if this would therefore indicate a change in the equilibrium of distribution due to increased cytoplasmic expression. Statistical analysis showed a significant correlation between high cytoplasmic LIMD1 expression and high nuclear LIMD1 expression (p < 0.0001).…”

Section: Limd1 Has Distinct Patterns Of Expression and Subcellular Lomentioning

confidence: 99%

“…19 LIMD1 blocks tumour growth and is downregulated in all human lung cancer samples tested. 19 These data indicate LIMD1 is a TSG and its loss may promote lung carcinogenesis.…”

mentioning

confidence: 98%

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Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Spendlove¹,

Al‐Attar²,

Watherstone³

et al. 2008

Intl Journal of Cancer

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The tumour suppressor gene (TSG) LIM domain containing protein 1 (LIMD1) has been associated with transformation of epithelial cells of the lung and its expression is downregulated in all lung tumour samples tested compared to normal lung matched controls. In the first study of its kind we used an anti-LIMD1 specific monoclonal antibody to investigate expression/localisation of the LIMD1 protein in a well-characterised tissue microarray of breast cancers and normal adjacent epithelia. Comparison of tumour with adjacent normal and distant normal tissue demonstrated that LIMD1 expression is moderate to high compared to tumour. There was also a significant correlation with histological grade (p 5 0.0001), tumour size (p 5 0.013) and tumour type (p 5 0.004) indicating an association with aggressive disease. Cytoplasmic LIMD1 expression was seen in 99.3% of cases, with 43.1% showing both nuclear and cytoplasmic localisation. Absence/loss of nuclear staining showed a strong correlation with patient survival and was indicative of poor prognosis (p 5 0.033). There was no association with lymph node status and other clinicopathological parameters. Nuclear staining was more pronounced in better prognosis tumours and normal tissue. This study demonstrates that LIMD1 represents a novel prognostic marker for breast cancer. Combined with the fact that LIMD1 expression is downregulated in lung cancers this clearly indicates that LIMD1 may represent a critical TSG, the function of which is deregulated via overall loss of expression and/or relocalisation within the cell during tumour development. The possible functions of LIMD1 localisation within the nucleus and cytoplasm and its relationship to tumour prognosis are discussed. ' 2008 Wiley-Liss, Inc.Key words: LIMD1; Ajuba; breast cancer; E-cadherin; tissue microarray; prognostic indicator Breast cancer is the most common cause of cancer-related death in women in the western world. Alterations in tumour suppressor genes (TSG) and oncogenes are common causes for the higher proliferative rates and pathogenic characteristics associated with tumour development. Cytogenetics and allelotyping have shown that allelic loss from several distinct regions on chromosome 3p, including 3p25, 3p21-22, 3p21.3, 3p12-13 and 3p14, are the earliest and most frequent genomic abnormalities involved in a wide spectrum of major epithelial cancers of lung 1-6 and breast tissues 7-9 as well as many other epithelial derived cancers. [10][11][12][13] Specifically the 3p21.3 gene cluster contains many TSG and oncogenes and is a region of major loss of heterozygosity in lung cancers. [14][15][16] Abnormalities at the 3p21.3 chromosomal region include homozygous deletions, loss of heterozygosity and expressional deficiencies that can be induced through methylation of promoters, altered mRNA transcripts and loss of protein translocation. 17 The chromosome 3 commonly eliminated region (C3CER1) is located within the 3p21.3 gene cluster. The C3CER1 contains several putative TSG and is eliminated in many forms o...

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Section: Limd1 Expression In Normal Breast Tissuesupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

Section: Limd1 Has Distinct Patterns Of Expression and Subcellular Lomentioning

confidence: 99%

“…19 LIMD1 blocks tumour growth and is downregulated in all human lung cancer samples tested. 19 These data indicate LIMD1 is a TSG and its loss may promote lung carcinogenesis.…”

mentioning

confidence: 98%

See 3 more Smart Citations

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Spendlove¹,

Al‐Attar²,

Watherstone³

et al. 2008

Intl Journal of Cancer

Self Cite

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LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control

Stroka

2022

FEBS Letters

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The LIM-domain protein Ajuba is associated with cell proliferation, a fundamental process of tissue regeneration and cancer. We report that in the liver, Ajuba expression is increased during regeneration and in tumour cells and tissues. Knockout of Ajuba using CRISPR/Cas9 is embryonic lethal in mice. shRNA targeting of Ajuba reduces cell proliferation, delays cell entry into Sphase, reduces cell survival and tumour growth in vivo and increases expression of the DNA damage marker γH2AX. Ajuba binding partners include proteins involved in DNA replication and damage, such as SKP2, MCM2, MCM7 and RPA70. Taken together, our data support that Ajuba promotes liver cell proliferation associated with development, regeneration and tumour growth and is involved in DNA replication and damage repair.

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WT1‐interacting protein inhibits cell proliferation and tumorigenicity in non‐small‐cell lung cancer via the AKT/FOXO1 axis

Qiu

et al. 2019

Molecular Oncology

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Lung cancer is the most common cancer and the leading cause of cancer‐related death worldwide; hence, it is imperative that the mechanisms underlying the malignant properties of lung cancer be uncovered in order to efficiently treat this disease. Increasing evidence has shown that WT1‐interacting protein (WTIP) plays important roles both physiologically and pathologically in humans; however, the role of WTIP in cancer is unknown. Here, we investigated the role and mechanism of WTIP in cell proliferation and tumorigenesis of non‐small‐cell lung cancer (NSCLC). We report that WTIP is a tumor suppressor in human NSCLC. We found that WTIP expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls; this reduction was largely attributed to promoter hypermethylation. Downregulation of WTIP significantly correlates with poor prognosis and predicts a shorter overall survival and progression‐free survival among NSCLC patients. Moreover, ectopic overexpression of WTIP dramatically inhibits cell proliferation and tumorigenesis in vitro and in vivo ; conversely, depletion of WTIP expression shows the opposite effects. Mechanistically, WTIP impairs AKT phosphorylation and activation, leading to enhanced expression and transcriptional activity of FOXO1, which further increases p21Cip1 and p27Kip1, and decreases cyclin D1, which consequently results in cell cycle arrest. Collectively, the results of the current study indicate that WTIP is an important proliferation‐related gene and that WTIP expression may represent a novel prognostic biomarker for NSCLC.

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LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at chromosome 3p21.3, binds pRB and represses E2F-driven transcription

Cited by 78 publications

References 38 publications

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control

WT1‐interacting protein inhibits cell proliferation and tumorigenicity in non‐small‐cell lung cancer via the AKT/FOXO1 axis

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