Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression

La, Ping; Desmond, Angela; Hou, Zhaoyuan; Silva, A C; Schnepp, Robert W.; Hua, Xianxin

doi:10.1038/sj.onc.1209400

Cited by 87 publications

(73 citation statements)

References 30 publications

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“…None of these appeared in our list, perhaps because of differences between whole embryos and MEFs. Menin-null MEFs, immortalized with retrovirus expressing human papillomaviral E6 and E7, and infected with retrovirus expressing menin, led to the identification of 25 transcripts each with >2-fold down (18) and up (12). Of these, Sdfr2 and Lgals3 were also found to be in our list of underexpressed and overexpressed transcripts, respectively, in menin-null MEFs.…”

Section: Consequence Of Gene Expression Changes On Menin Lossmentioning

confidence: 91%

“…We treated a WT (W10) and a menin-null (N47) MEF cell line with varying amounts (0, 2.5, 5, and 10 ng/mL) of TGF-h for varying lengths of time (12,24, and 48 h), and expression of the three extracellular matrix proteins, Postn, Cspg2, and Fbln2, was evaluated (Fig. 6).…”

Section: Tgf-b -Induced Menin-mediated Gene Expression Changesmentioning

confidence: 99%

“…Interaction of menin with Smad3 is reported to result in activation of transforming growth factor-h (TGF-h)-induced transcription (8), and the interaction of menin with Smad1, Smad3, Smad5, and Runx2 may participate in the TGF-hmediated and bone morphogenetic protein-2 -mediated pathways of commitment of multipotential mesenchymal stem cells to osteoblast lineage (9)(10)(11). Previous studies of gene expression in tumors, cell lines, and embryos have identified nonoverlapping sets of gene(s), whose expression is affected by menin (5,12,13). A recent report of chromatin immunoprecipitationon-chip analysis has identified thousands of menin-binding promoter targets in the human genome (14).…”

Section: Introductionmentioning

confidence: 99%

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Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes

Ji¹,

Prasad²,

Novotny³

et al. 2007

Molecular Cancer Research

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized primarily by endocrine tumors of the parathyroids, anterior pituitary, and enteropancreatic endocrine tissues. Affected individuals carry a germ-line loss-of-function mutation of the MEN1 gene, and tumors arise after loss of the second allele. Homozygous loss of Men1 in the germ line of mice results in early embryonic lethality, with defective development of neural tube, heart, liver, and craniofacial structures. We generated immortalized wild-type (WT) and menin-null mouse embryo fibroblast (MEF) cell lines and evaluated their characteristics, including global expression patterns. The WT and menin-null cell lines were aneuploid, and the nulls did not display tumorigenic characteristics in soft agar assay. Expression arrays in menin-null MEFs revealed altered expression of several extracellular matrix proteins that are critical in organogenesis. Specifically, transcripts for fibulin 2 (Fbln2), periostin (Postn), and versican [chondroitin sulfate proteoglycan (Cspg2)], genes critical for the developing heart and known to be induced by transforming growth factor-B (TGF-B), were decreased in their expression in menin-null MEFs. Fbln2 expression was the most affected, and the reduction in menin-null MEFs for Fbln2, Postn, and Cspg2 was 16.18-, 5.37-, and 2.15-fold, respectively. Menin-null MEFs also showed poor response to TGF-B -induced Smad3-mediated transcription in a reporter assay, supporting a role for menin in this pathway. Postn and Cspg2 expression in WT, unlike in null MEFs, increased on TGF-B treatment. The expression changes associated with the loss of the tumor suppressor menin provide insights into the defective organogenesis observed during early embryonic development in Men1-null mouse embryos.

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Section: Consequence Of Gene Expression Changes On Menin Lossmentioning

confidence: 91%

Section: Tgf-b -Induced Menin-mediated Gene Expression Changesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes

Ji¹,

Prasad²,

Novotny³

et al. 2007

Molecular Cancer Research

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“…Menin is predominantly located in the nucleus and contains two classic NLSs, NLS1 and NLS2 (18). Classic NLSs comprise positively charged amino acid residues which bind to a soluble transport receptor complex made up of importins α and β, causing the protein to be translocated to the nucleus (19).…”

Section: Discussionmentioning

confidence: 99%

Expression and subcellular localization of menin in human cancer cells

Ren

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. The aim of this study was to elucidate the expression and localization of menin, a protein encoded by the multiple endocrine neoplasia type I (MEN1) gene, in 13 human cancer cell lines. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression of the menin gene. The localization of the menin protein was detected by immunofluorescence microscopy. Western blotting was used to determine the quantity of menin in the nucleus, cytosol and membrane of the cells. RT-PCR revealed that menin was expressed in all the cell lines examined in this study. Immunofluorescence microscopy revealed that menin was located primarily in the nucleus. In the GES-1 (transformed human gastric epithelium), MCF-7 (breast cancer), SGH44 (brain glioma) and HeLa (cervical cancer) cell lines, menin was also found to be localized to the membrane, cytosol and nucleus. Moreover, in SGH44 cells more menin was located in the cytosol than the nucleus. Similar findings were obtained by western blotting. In the GES-1 and MKN-28 cells undergoing octreotide treatment, cytoplasmic menin was significantly increased compared with the control groups. Therefore, we suggest that menin is expressed in a number of human cancer cell lines and that the cytosolic distribution increases when the cells undergo octreotide treatment, indicating a new role for menin.

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“…Indeed, allelic losses at chromosome 11q13, which includes the locus of MEN1 gene (Larsson et al 1988), are found in 46% of sporadic PETs (Speel et al 1999, Rigaud et al 2001, while the reported frequency of MEN1 mutations is lower, thus suggesting that additional oncosuppressor genes lie on this chromosomal arm (Eubanks et al 1994, Chakrabarti et al 1998, Gortz et al 1999, Jonkers et al 2006. MEN1 gene encodes for menin, a 610 amino acid protein (Chandrasekharappa et al 1997, Lemmens et al 1997 that is ubiquitously expressed in adult tissues (Chandrasekharappa et al 1997) and located prevalently in the nucleus via three nuclear localization signals (NLS1, NLS2, and NLSa) in its C-terminal fragment (Guru et al 1998, La et al 2006. Cavallari et al (2003) provided the first description of the immunohistochemical expression pattern of menin in human pancreas using indirect immunofluorescence (IF) on frozen tissues, showing that the protein is mainly localized into the nucleus of all pancreatic cell types.…”

Section: Introductionmentioning

confidence: 99%

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

Corbo¹,

Dalai²,

Scardoni³

et al. 2010

Endocrine-Related Cancer

145

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Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical-pathological parameters. Twentyseven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein-protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.

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Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression

Cited by 87 publications

References 30 publications

Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes

Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes

Expression and subcellular localization of menin in human cancer cells

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

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