High Frequency of <i>LMAN1</i> Abnormalities in Colorectal Tumors with Microsatellite Instability

Roeckel, Nina; Woerner, Stefan M.; Kloor, Matthias; Yuan, Yan P.; Patsos, Georgios; Gromes, Roland; Kopitz, Juergen; Gebert, Johannes

doi:10.1158/0008-5472.can-08-3314

Cited by 25 publications

(23 citation statements)

References 38 publications

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“…Sec16 was found to be upregulated approximately twofold in colonic cancer samples compared with its expression in healthy tissue (Wiśniewski et al, 2012). This was not due to general upregulation of all secretory pathway components, as ERGIC-53 was downregulated (Wiśniewski et al, 2012), which is in agreement with earlier reports on the link between ERGIC-53 and cancer (Roeckel et al, 2009). Our findings demonstrate that changes in the number of ERES are part of the cellular response to mitogen treatment and therefore imply a close link between the regulation of secretion and cell growth and proliferation.…”

Section: Discussionsupporting

confidence: 91%

Regulation of Sec16 levels and dynamics links proliferation and secretion

Tillmann

Reiterer

Baschieri

et al. 2014

Journal of Cell Science

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We currently lack a broader mechanistic understanding of the integration of the early secretory pathway with other homeostatic processes such as cell growth. Here, we explore the possibility that Sec16A, a major constituent of endoplasmic reticulum exit sites (ERES), acts as an integrator of growth factor signaling. Surprisingly, we find that Sec16A is a short-lived protein that is regulated by growth factors in a manner dependent on Egr family transcription factors. We hypothesize that Sec16A acts as a central node in a coherent feed-forward loop that detects persistent growth factor stimuli to increase ERES number. Consistent with this notion, Sec16A is also regulated by short-term growth factor treatment that leads to increased turnover of Sec16A at ERES. Finally, we demonstrate that Sec16A depletion reduces proliferation, whereas its overexpression increases proliferation. Together with our finding that growth factors regulate Sec16A levels and its dynamics on ERES, we propose that this protein acts as an integrator linking growth factor signaling and secretion. This provides a mechanistic basis for the previously proposed link between secretion and proliferation.

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Section: Discussionsupporting

confidence: 91%

Regulation of Sec16 levels and dynamics links proliferation and secretion

Tillmann

Reiterer

Baschieri

et al. 2014

Journal of Cell Science

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“…The systematic identification of frameshift mutations in cMNR is an effective way to identify target genes in MSI‐H cancers. We and others have searched for mononucleotide repeats in the gene data base and identified several target genes 18, 36–39. However, a second gene database search is needed to determine whether the MNR is located in the coding region and mutation analysis is needed to confirm that the genes are related to MSI‐H tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Identification of frequently mutated genes with relevance to nonsense mediated mRNA decay in the high microsatellite instability cancers

Shin

You

Lee

et al. 2010

Intl Journal of Cancer

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Frameshift mutations at coding mononucleotide repeats (cMNR) are frequent in high‐microsatellite instability (MSI‐H) cancers. Frameshift mutations in cMNR result in the formation of a premature termination codon (PTC) in the transcribed mRNA, and these abnormal mRNAs are generally degraded by nonsense mediated mRNA decay (NMD). We have identified novel genes that are frequently mutated at their cMNR by blocking NMD in two MSI‐H cancer cell lines. After blocking NMD, we screened for differentially expressed genes using DNA microarrays, and then used database analysis to select 28 candidate genes containing cMNR with more than 9 nucleotide repeats. cMNR mutations have not been previously reported in MSI‐H cancers for 15 of the 28 genes. We analyzed the cMNR mutation of each of the 15 genes in 10 MSI‐H cell lines and 21 MSI‐H cancers, and found frequent mutations of 12 genes in MSI‐H cell lines and cancers, but not in microsatellite stable (MSS) cancers. Among these genes, the most frequently mutated in MSI‐H cell lines were MLL3 (70%), PHACTR4 (70%), RUFY2 (50%) and TBC1D23 (50%). MLL3, which has already been implicated in cancer, had the highest mutation frequency in MSI‐H cancers (48%). Our combined approach of NMD block, database search, and mutation analysis has identified a large number of genes mutated in their cMNR in MSI‐H cancers. The identified mutations are expected to contribute to MSI‐H tumorigenesis by causing an absence of gene expression or low gene dosage effects.

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“…Unfortunately DNA samples from his parents were not available for analysis. Interestingly, this same (A) 9 repeat was recently reported to be frequently mutated in microsatellite unstable colon cancer cell lines and tissues (24). …”

Section: Resultsmentioning

confidence: 89%

Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1

et al. 2013

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Introduction Percutaneous coronary intervention (PCI) in patients with congenital coagulation factor deficiencies presents a unique challenge. They are not only at increased risk of perioperative bleeding but can also suffer thrombosis of the stent since preventive anticoagulation and antiplatelet therapy is difficult. Several cases of successful PCI have been described in patients with hemophilias A and B, but there are no reports in patients with combined coagulation factor deficiencies. Aim We used PCI to treat the coronary artery disease in a patient with the combined deficiency of factor V and factor VIII (F5F8D) and analyzed the molecular basis of the disorder for this patient. Methods A 68 year old patient was admitted for urgent PCI with bare metal stent placement after the diagnosis of the combined deficiency of F5F8D. Peripheral blood DNA was extracted for the sequence analysis of LMAN1 and MCFD2 genes. Mutation in LMAN1 was confirmed by molecular cloning of the PCR product and resequencing of the resulting clones. Results The patient underwent successful PCI with good long-term outcome. He tolerated well anticoagulation therapy with unfractionated heparin and double antiplatelet therapy while he was initially supported with fresh frozen plama and recombinant FVIII. Molecular analysis revealed that the patient carries unusual compound heterozygous frameshift mutations on the same microsatellite repeat region in exon 8 of LMAN1, one of which is a novel mutation (c.912delA). Conclusion Our results suggest that patients with F5F8D can safely undergo PCI for coronary artery disease, with the treatment individualized to the specific patient.

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High Frequency of LMAN1 Abnormalities in Colorectal Tumors with Microsatellite Instability

Cited by 25 publications

References 38 publications

Regulation of Sec16 levels and dynamics links proliferation and secretion

Regulation of Sec16 levels and dynamics links proliferation and secretion

Identification of frequently mutated genes with relevance to nonsense mediated mRNA decay in the high microsatellite instability cancers

Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1

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