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Communications Biology Oct 2023Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest...
Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest resistance to chemotherapy and radiotherapy. Vasculogenic mimicry (VM) provides tumor cells with a blood supply independent of endothelial cells and greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. Vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial cadherin (VE-cadherin) are currently recognized molecular markers of VM in tumors. In the present study, we show that pseudogene MAPK6P4 deficiency represses VEGFR2 and VE-cadherin protein expression levels, as well as inhibits the proliferation, migration, invasion, and VM development of GBM cells. The MAPK6P4-encoded functional peptide P4-135aa phosphorylates KLF15 at the S238 site, promoting KLF15 protein stability and nuclear entry to promote GBM VM formation. KLF15 was further confirmed as a transcriptional activator of LDHA, where LDHA binds and promotes VEGFR2 and VE-cadherin lactylation, thereby increasing their protein expression. Finally, we used orthotopic and subcutaneous xenografted nude mouse models of GBM to verify the inhibitory effect of the above factors on GBM VM development. In summary, this study may represent new targets for the comprehensive treatment of glioma.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Endothelial Cells; Glioblastoma; Glioma; Neovascularization, Pathologic; Pseudogenes; Vascular Endothelial Growth Factor Receptor-2
PubMed: 37853052
DOI: 10.1038/s42003-023-05438-1 -
Experimental Hematology Nov 2021Pseudogenes are DNA regions comprising defective copies of functional genes, the majority of which were generated by RNA- or DNA-level duplications. They exist across... (Review)
Review
Pseudogenes are DNA regions comprising defective copies of functional genes, the majority of which were generated by RNA- or DNA-level duplications. They exist across almost all forms of life and account for about one-quarter of the annotated genes in the human genome. Although these have been considered nonfunctional for decades, a growing number of pseudogenes have been found to be transcribed and to play crucial regulatory roles. Accumulating evidence indicates that they regulate gene expression through molecular interactions at the protein, RNA, and DNA levels. However, pseudogenes are often excluded in multiple genomewide analyses and functional screening, and their biological activities remain to be systematically disclosed. Here, we summarize the features of and progress of research on pseudogenes, in addition to discussing what is unknown about these genetic elements. Our previous findings, together with evidence of their poor conservation, prompted us to propose that pseudogenes may contribute to primate- or human-specific regulation, especially in hematopoiesis.
Topics: Animals; Gene Expression Regulation, Developmental; Gene Expression Regulation, Leukemic; Hematopoiesis; Humans; Leukemia; Pseudogenes
PubMed: 34517065
DOI: 10.1016/j.exphem.2021.09.001 -
Genes Aug 2021Once considered nonfunctional, pseudogene transcripts are now known to provide valuable information for cancer susceptibility, including head and neck cancer (HNC), a... (Review)
Review
Once considered nonfunctional, pseudogene transcripts are now known to provide valuable information for cancer susceptibility, including head and neck cancer (HNC), a serious health problem worldwide, with about 50% unimproved overall survival over the last decades. The present review focuses on the role of pseudogene transcripts involved in HNC risk and prognosis. We combined current literature and analyses from The Cancer Genome Atlas (TCGA) database to identify the most deregulated pseudogene transcripts in HNC and their genetic variations. We then built a co-expression network and performed gene ontology enrichment analysis to better understand the pseudogenes' interactions and pathways in HNC. In the literature, few pseudogenes have been studied in HNC. Our analysis identified 370 pseudogene transcripts associated with HNC, where , , , , , , , , and were found to be the most deregulated and presented several genetic alterations. , , and pseudogenes were predicted to interact with 12 genes known to participate in HNC, was predicted to interact with the gene, and pseudogene was predicted to interact with and genes. The identified pseudogenes were associated with cancer biology pathways involving cell communication, response to stress, cell death, regulation of the immune system, regulation of gene expression, and Wnt signaling. Finally, we assessed the prognostic values of the pseudogenes with the Kaplan-Meier Plotter database, and found that expression of , , , , and pseudogenes were associated with patients' survival. Due to pseudogene transcripts' potential for cancer diagnosis, progression, and as therapeutic targets, our study can guide new research to HNC understanding and development of new target therapies.
Topics: Biomarkers, Tumor; Computational Biology; Disease Progression; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Kaplan-Meier Estimate; Neoplasm Proteins; Prognosis
PubMed: 34440428
DOI: 10.3390/genes12081254 -
Immunogenetics Jun 2023Glycophorins are transmembrane proteins of red blood cells (RBCs), heavily glycosylated on their external-facing surface. In humans, there are four glycophorin proteins,... (Review)
Review
Glycophorins are transmembrane proteins of red blood cells (RBCs), heavily glycosylated on their external-facing surface. In humans, there are four glycophorin proteins, glycophorins A, B, C and D. Glycophorins A and B are encoded by two similar genes GYPA and GYPB, and glycophorin C and glycophorin D are encoded by a single gene, GYPC. The exact function of glycophorins remains unclear. However, given their abundance on the surface of RBCs, it is likely that they serve as a substrate for glycosylation, giving the RBC a negatively charged, complex glycan "coat". GYPB and GYPE (a closely related pseudogene) were generated from GYPA by two duplication events involving a 120-kb genomic segment between 10 and 15 million years ago. Non-allelic homologous recombination between these 120-kb repeats generates a variety of duplication alleles and deletion alleles, which have been systematically catalogued from genomic sequence data. One allele, called DUP4, encodes the Dantu NE blood type and is strongly protective against malaria as it alters the surface tension of the RBC membrane. Glycophorins interact with other infectious pathogens, including viruses, as well as the malarial parasite Plasmodium falciparum, but the role of glycophorin variation in mediating the effects of these pathogens remains underexplored.
Topics: Humans; Glycophorins; Erythrocytes; Membrane Proteins; Communicable Diseases; Genetic Variation
PubMed: 36224278
DOI: 10.1007/s00251-022-01280-7 -
Frontiers in Cell and Developmental... 2020Pseudogenes, abundant in the human genome, are traditionally considered as non-functional "junk genes." However, recent studies have revealed that pseudogenes act as key... (Review)
Review
Pseudogenes, abundant in the human genome, are traditionally considered as non-functional "junk genes." However, recent studies have revealed that pseudogenes act as key regulators at DNA, RNA or protein level in diverse human disorders (including cancer), among which pseudogene-derived long non-coding RNA (lncRNA) transcripts are extensively investigated and has been reported to be frequently dysregulated in various types of human cancer. Growing evidence demonstrates that pseudogene-derived lncRNAs play important roles in cancer initiation and progression by serving as competing endogenous RNAs (ceRNAs) through competitively binding to shared microRNAs (miRNAs), thus affecting both their cognate genes and unrelated genes. Herein, we retrospect those current findings about expression, functions and potential ceRNA mechanisms of pseudogene-derived lncRNAs in human cancer, which may provide us with some crucial clues in developing potential targets for cancer therapy in the future.
PubMed: 32185172
DOI: 10.3389/fcell.2020.00085 -
Molecular Biology and Evolution Jul 2022Prokaryotic genomes are usually densely packed with intact and functional genes. However, in certain contexts, such as after recent ecological shifts or extreme...
Prokaryotic genomes are usually densely packed with intact and functional genes. However, in certain contexts, such as after recent ecological shifts or extreme population bottlenecks, broken and nonfunctional gene fragments can quickly accumulate and form a substantial fraction of the genome. Identification of these broken genes, called pseudogenes, is a critical step for understanding the evolutionary forces acting upon, and the functional potential encoded within, prokaryotic genomes. Here, we present Pseudofinder, an open-source software dedicated to pseudogene identification and analysis in bacterial and archaeal genomes. We demonstrate that Pseudofinder's multi-pronged, reference-based approach can detect a wide variety of pseudogenes, including those that are highly degraded and typically missed by gene-calling pipelines, as well newly formed pseudogenes containing only one or a few inactivating mutations. Additionally, Pseudofinder can detect genes that lack inactivating substitutions but experiencing relaxed selection. Implementation of Pseudofinder in annotation pipelines will allow more precise estimations of the functional potential of sequenced microbes, while also generating new hypotheses related to the evolutionary dynamics of bacterial and archaeal genomes.
Topics: Bacteria; Genome, Archaeal; Prokaryotic Cells; Pseudogenes; Software
PubMed: 35801562
DOI: 10.1093/molbev/msac153 -
Cancers Aug 2023Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode.... (Review)
Review
Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode. Initially disregarded as "junk DNA" due to their perceived lack of functionality, research on their biological roles has been hindered by this assumption. Nevertheless, recent focus has shifted towards these molecules due to their abnormal expression in cancer phenotypes. In this review, our objective is to provide a thorough overview of the current understanding of pseudogene formation, the mechanisms governing their expression, and the roles they may play in promoting tumorigenesis.
PubMed: 37627052
DOI: 10.3390/cancers15164024 -
Frontiers in Oncology 2022Pseudogenes have been considered as non-functional genes. However, peptides and long non-coding RNAs produced by pseudogenes are expressed in different tumors. Moreover,... (Review)
Review
Pseudogenes have been considered as non-functional genes. However, peptides and long non-coding RNAs produced by pseudogenes are expressed in different tumors. Moreover, the dysregulation of pseudogenes is associated with cancer, and their expressions are higher in tumors compared to normal tissues. Recent studies show that pseudogenes can influence the liquid phase condensates formation. Liquid phase separation involves regulating different epigenetic stages, including transcription, chromatin organization, 3D DNA structure, splicing, and post-transcription modifications like mA. Several membrane-less organelles, formed through the liquid phase separate, are also involved in the epigenetic regulation, and their defects are associated with cancer development. However, the association between pseudogenes and liquid phase separation remains unrevealed. The current study sought to investigate the relationship between pseudogenes and liquid phase separation in cancer development, as well as their therapeutic implications.
PubMed: 35875144
DOI: 10.3389/fonc.2022.912282 -
Cells Nov 2020Ferritin, the principal intracellular iron-storage protein localized in the cytoplasm, nucleus, and mitochondria, plays a major role in iron metabolism. The encoding... (Review)
Review
Ferritin, the principal intracellular iron-storage protein localized in the cytoplasm, nucleus, and mitochondria, plays a major role in iron metabolism. The encoding ferritin genes are members of a multigene family that includes some pseudogenes. Even though pseudogenes have been initially considered as relics of ancient genes or junk DNA devoid of function, their role in controlling gene expression in normal and transformed cells has recently been re-evaluated. Numerous studies have revealed that some pseudogenes compete with their parental gene for binding to the microRNAs (miRNAs), while others generate small interference RNAs (siRNAs) to decrease functional gene expression, and still others encode functional mutated proteins. Consequently, pseudogenes can be considered as actual master regulators of numerous biological processes. Here, we provide a detailed classification and description of the structural features of the ferritin pseudogenes known to date and review the recent evidence on their mutual interrelation within the complex regulatory network of the ferritin gene family.
Topics: Animals; Ferritins; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; MicroRNAs; Neoplasms; Oxidoreductases; Pseudogenes; RNA, Small Interfering
PubMed: 33260500
DOI: 10.3390/cells9122554 -
Nucleic Acids Research Jan 2023The HUGO Gene Nomenclature Committee (HGNC) assigns unique symbols and names to human genes. The HGNC database (www.genenames.org) currently contains over 43 000...
The HUGO Gene Nomenclature Committee (HGNC) assigns unique symbols and names to human genes. The HGNC database (www.genenames.org) currently contains over 43 000 approved gene symbols, over 19 200 of which are assigned to protein-coding genes, 14 000 to pseudogenes and nearly 9000 to non-coding RNA genes. The public website, www.genenames.org, displays all approved nomenclature within Symbol Reports that contain data curated by HGNC nomenclature advisors and links to related genomic, clinical, and proteomic information. Here, we describe updates to our resource, including improvements to our search facility and new download features.
Topics: Humans; Databases, Genetic; Genome; Genomics; Proteomics; Pseudogenes; Terminology as Topic
PubMed: 36243972
DOI: 10.1093/nar/gkac888