Comprehensive Analysis of MEN1 Mutations and Their Role in Cancer

Nelakurti, Devi D.; Pappula, Amrit L; Rajasekaran, Swetha; Miles, Wayne; Petreaca, Ruben C.

doi:10.3390/cancers12092616

Cited by 21 publications

(21 citation statements)

References 120 publications

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“…Protein alignments of the DGAT2 isoforms were generated using COBALT ( , accessed on 4 March 2021) as described previously [ 18 , 19 ]. The lollipop figures were made as reported earlier [ 20 , 21 ].…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Genetic Analysis of DGAT2 Mutations and Gene Expression Patterns in Human Cancers

Graber

Barta

Wood

et al. 2021

Biology

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DGAT2 is a transmembrane protein encoded by the DGAT2 gene that functions in lipid metabolism, triacylglycerol synthesis, and lipid droplet regulation. Cancer cells exhibit altered lipid metabolism and mutations in DGAT2 may contribute to this state. Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we analyzed all cancer genetic DGAT2 alterations, including mutations, copy number variations and gene expression. We find that several DGAT2 mutations fall within the catalytic site of the enzyme. Using the Variant Effect Scoring Tool (VEST), we identify multiple mutations with a high likelihood of contributing to cellular transformation. We also found that D222V is a mutation hotspot neighboring a previously discovered Y223H mutation that causes Axonal Charcot-Marie-Tooth disease. Remarkably, Y223H has not been detected in cancers, suggesting that it is inhibitory to cancer progression. We also identify several single nucleotide polymorphisms (SNP) with high VEST scores, indicating that certain alleles in human populations have a pathogenic predisposition. Most mutations do not correlate with a change in gene expression, nor is gene expression dependent on high allele copy number. However, we did identify eight alleles with high expression levels, suggesting that at least in certain cases, the excess DGAT2 gene product is not inhibitory to cellular proliferation. This work uncovers unknown functions of DGAT2 in cancers and suggests that its role may be more complex than previously appreciated.

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Section: Methodsmentioning

confidence: 99%

Comprehensive Genetic Analysis of DGAT2 Mutations and Gene Expression Patterns in Human Cancers

Graber

Barta

Wood

et al. 2021

Biology

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“…Most of these alterations include non-sense and frameshift mutations and, in minor fraction, also splicing defects and large deletions, causing menin inactivation due to the premature protein truncation or inhibition of its expression. About 25% of MEN1 mutations are missense variants whose consequences at the level of structure and function are not easily conceivable as for the variants mentioned above [ 12 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Investigating the Effects of Amino Acid Variations in Human Menin

et al. 2022

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Human menin is a nuclear protein that participates in many cellular processes, as transcriptional regulation, DNA damage repair, cell signaling, cell division, proliferation, and migration, by interacting with many other proteins. Mutations of the gene encoding menin cause multiple endocrine neoplasia type 1 (MEN1), a rare autosomal dominant disorder associated with tumors of the endocrine glands. In order to characterize the structural and functional effects at protein level of the hundreds of missense variations, we investigated by computational methods the wild-type menin and more than 200 variants, predicting the amino acid variations that change secondary structure, solvent accessibility, salt-bridge and H-bond interactions, protein thermostability, and altering the capability to bind known protein interactors. The structural analyses are freely accessible online by means of a web interface that integrates also a 3D visualization of the structure of the wild-type and variant proteins. The results of the study offer insight into the effects of the amino acid variations in view of a more complete understanding of their pathological role.

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Section: Introductionmentioning

confidence: 99%

“…Menin 1 (MEN1) is a tumor suppressor that can function in multiple biological processes, such as cell proliferation, migration, and DNA damage repair [ 13 , 14 ]. MEN1 contains four functional domains: an N-terminal domain, thumb domain, palm domain, and C-terminus domain (CTD) [ 13 , 14 ]. The CTD domain determines the nuclear localization of MEN1 because it contains three nuclear localization sequences, while the other three domains interact with different proteins [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

A Hypoxia-Induced SCFFBXL1 E3 Ligase Ubiquitinates and Degrades the MEN1 Tumor Suppressor to Promote Colorectal Cancer Tumorigenesis

2022

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Emerging evidence has shown that SKP1-cullin-1-F-box-protein (SCF) E3 ligases contribute to the pathogenesis of different cancers by mediating the ubiquitination and degradation of tumor suppressors. However, the functions of SCF E3 ligases in the pathogenesis of colorectal cancer (CRC) remain obscure. Materials and MethodsThe cancerous and adjacent noncancerous tissues from CRC patients were collected, and protein levels were analyzed. Lentiviral short hairpin RNA (shRNA) and plasmid transfection were used to knock down and overexpress gene expression in CRC cell lines. Immunoprecipitation (IP), mass spectrometry, and co-IP analyses were used to determine protein interactions and the assembly of the SCF complex. Cell proliferation, migration, and tumor xenograft assays were performed to examine the effects of SCF members on CRC cell growth in vitro and in vivo. ResultsHypoxia activated the docking of HIF1a onto the CUL1 promoter and induced CUL1 expression in CRC cells. CUL1 coupled with RBX1, SKP1, and FBXL1 to assemble the SCF FBXL1 complex in CRC biopsies and cells. The SCF FBXL1 E3 ligase specifically ubiquitinated and degraded the MEN1 tumor suppressor. Knockdown of HIF1a or SCF FBXL1 members, or blockage of SCF FBXL1 by two inhibitors (DT204 and SZLP1-41) caused the accumulation of MEN1 protein and led to a significant decrease in cell proliferation and migration in vitro and tumor growth in vivo. ConclusionThe SCF FBXL1 E3 ligase is required for the ubiquitination of MEN1, and disruption of this complex may represent a new therapeutic strategy for the treatment of CRC.

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Comprehensive Analysis of MEN1 Mutations and Their Role in Cancer

Cited by 21 publications

References 120 publications

Comprehensive Genetic Analysis of DGAT2 Mutations and Gene Expression Patterns in Human Cancers

Comprehensive Genetic Analysis of DGAT2 Mutations and Gene Expression Patterns in Human Cancers

Investigating the Effects of Amino Acid Variations in Human Menin

A Hypoxia-Induced SCFFBXL1 E3 Ligase Ubiquitinates and Degrades the MEN1 Tumor Suppressor to Promote Colorectal Cancer Tumorigenesis

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