Enhanced expression of the nuclear envelope LAP2 transcriptional repressors in normal and malignant activated lymphocytes

Somech, Raz; Gal‐Yam, Einav Nili; Shaklai, Sigal; Geller, Orit; Amariglio, Ninette; Rechavi, Gideon; Simon, Amos J.

doi:10.1007/s00277-007-0275-9

Cited by 21 publications

(17 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4d,e) were spotted on glass cover slips and analysed for lamin A, lamin C and prelamin A expression. In agreement with earlier reports on lamin A/C deficiency in granulocytes 22 and lamin A/C expression in lymphocytes, 23 we detected a similar distribution for lamin A/C in the patient (Fig. 4a,b) and healthy control (Fig.…”

Section: Resultssupporting

confidence: 93%

A newly identified splice site mutation inZMPSTE24causes restrictive dermopathy in the Middle East

Sander¹,

Salman

Geel

et al. 2008

British Journal of Dermatology

View full text Add to dashboard Cite

Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in-frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation.

show abstract

Section: Resultssupporting

confidence: 93%

A newly identified splice site mutation inZMPSTE24causes restrictive dermopathy in the Middle East

Sander¹,

Salman

Geel

et al. 2008

British Journal of Dermatology

View full text Add to dashboard Cite

show abstract

“…However, its expression in normal gastrointestinal tract was rarely detected [47]. Overexpression of LAP2β was reported in various hematological malignant cells and neuroblastoma cells [17], [48]. Moreover, LAP2α is overexpressed in various solid cancers including larynx, lung, stomach, breast and colon cancer [19].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to these laminopathies, involvement of LAP2 in carcinogenesis has been described. For example, LAP2β has been shown to be involved in proliferation of malignant lymphocytes [12], [17], [18]. Moreover, overexpression of LAP2α was reported in larynx, lung, stomach, breast and colon cancer tissues [19].…”

Section: Introductionmentioning

confidence: 99%

LAP2 Is Widely Overexpressed in Diverse Digestive Tract Cancers and Regulates Motility of Cancer Cells

et al. 2012

View full text Add to dashboard Cite

BackgroundLamina-associated polypeptides 2 (LAP2) is a nuclear protein that connects the nuclear lamina with chromatin. Although its critical roles in genetic disorders and hematopoietic malignancies have been described, its expression and roles in digestive tract cancers have been poorly characterized.MethodsTo examine the expression of LAP2 in patient tissues, we performed immunohistochemistry and real-time PCR. To examine motility of cancer cells, we employed Boyden chamber, wound healing and Matrigel invasion assays. To reveal its roles in metastasis in vivo, we used a liver metastasis xenograft model. To investigate the underlying mechanism, a cDNA microarray was conducted.ResultsImmunohistochemistry in patient tissues showed widespread expression of LAP2 in diverse digestive tract cancers including stomach, pancreas, liver, and bile duct cancers. Real-time PCR confirmed that LAP2β is over-expressed in gastric cancer tissues. Knockdown of LAP2β did not affect proliferation of most digestive tract cancer cells except pancreatic cancer cells. However, knockdown of LAP2β decreased motility of all tested cancer cells. Moreover, overexpression of LAP2β increased motility of gastric and pancreatic cancer cells. In the liver metastasis xenograft model, LAP2β increased metastatic efficacy of gastric cancer cells and mortality in tested mice. cDNA microarrays showed the possibility that myristoylated alanine-rich C kinase substrate (MARCKS) and interleukin6 (IL6) may mediate LAP2β-regulated motility of cancer cells.ConclusionsFrom the above results, we conclude that LAP2 is widely overexpressed in diverse digestive tract cancers and LAP2β regulates motility of cancer cells and suggest that LAP2β may have utility for diagnostics and therapeutics in digestive tract cancers.

show abstract

“…In the critical-gene model, we identified the WHSC1 gene, which is deregulated by t(4;14) translocation and is associated with poor prognosis in MM; however, very little was known about the remaining 3 genes in myeloma. For instance, TMPO, is involved in the structural organization of the nuclear envelope, has been found deregulated in several hematologic tumors (35), and is included in the 17-gene signature of Zhan and colleagues (3), whereas KIF21B, encoding a motor protein essential to cellular transport, maps to 1q arm (1q32.1) whose amplification characterizes a significant fraction of high-risk MM tumors.…”

Section: Discussionmentioning

confidence: 99%

The Reconstruction of Transcriptional Networks Reveals Critical Genes with Implications for Clinical Outcome of Multiple Myeloma

Agnelli

Forcato

Ferrari

et al. 2011

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The combined use of microarray technologies and bioinformatics analysis has improved our understanding of biological complexity of multiple myeloma (MM). In contrast, the application of the same technology in the attempt to predict clinical outcome has been less successful with the identification of heterogeneous molecular signatures. Herein, we have reconstructed gene regulatory networks in a panel of 1,883 samples from MM patients derived from publicly available gene expression sets, to allow the identification of robust and reproducible signatures associated with poor prognosis across independent data sets.Experimental Design: Gene regulatory networks were reconstructed by using Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) and microarray data from seven MM data sets. Critical analysis of network components was applied to identify genes playing an essential role in transcriptional networks, which are conserved between data sets.Results: Network critical analysis revealed that (i) CCND1 and CCND2 were the most critical genes; (ii) CCND2, AIF1, and BLNK had the largest number of connections shared among the data sets; (iii) robust gene signatures with prognostic power were derived from the most critical transcripts and from shared primary neighbors of the most connected nodes. Specifically, a critical-gene model, comprising FAM53B, KIF21B, WHSC1, and TMPO, and a neighbor-gene model, comprising BLNK shared neighbors CSGALNACT1 and SLC7A7, predicted survival in all data sets with follow-up information.Conclusions: The reconstruction of gene regulatory networks in a large panel of MM tumors defined robust and reproducible signatures with prognostic importance, and may lead to identify novel molecular mechanisms central to MM biology. Clin Cancer Res; 17(23); 7402-12. Ó2011 AACR.

show abstract

Enhanced expression of the nuclear envelope LAP2 transcriptional repressors in normal and malignant activated lymphocytes

Cited by 21 publications

References 33 publications

A newly identified splice site mutation inZMPSTE24causes restrictive dermopathy in the Middle East

A newly identified splice site mutation inZMPSTE24causes restrictive dermopathy in the Middle East

LAP2 Is Widely Overexpressed in Diverse Digestive Tract Cancers and Regulates Motility of Cancer Cells

The Reconstruction of Transcriptional Networks Reveals Critical Genes with Implications for Clinical Outcome of Multiple Myeloma

Contact Info

Product

Resources

About