Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. To date, at least 9 differe...Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. To date, at least 9 different human diseases, which superficially seem to share little with one another, result from LMNA mutations. The position of the mutation within LMNA appears to be associated with the phenotypes. This review gives an overview of genotype-phenotype relationship and describes recent advances in animal models and pathogenic mechanisms.展开更多
Cell aging,the fundamental unit of biological decay,is responsible for senile disease. With the development of research,the mechanism of cell aging has been investigated in molecular level. Two hypotheses have emerged...Cell aging,the fundamental unit of biological decay,is responsible for senile disease. With the development of research,the mechanism of cell aging has been investigated in molecular level. Two hypotheses have emerged to explain the reason that lamins contribute to cell aging,one is the mechanical stress hypothesis,the other is the gene expression hypothesis. The latter proposes that mutations in A-type lamins lead to abnormal tissue-specific gene regulation. In recent years,the molecular mechanisms of lamins causing cell aging primarily include gene mutation,Zmpste24 mutation,CAAX mutation and other mutations. These mutations in the gene that encode nuclear lamins cause nuclear lamina damage directly and result in cell aging,which have been associated with several degenerative disorders.展开更多
The link of the metazoan nucleus to the actin cytoskeleton is highly important for actin polymerization and migration of multiple cell types as well as for mechanotransduction and even affects the cellular transcripto...The link of the metazoan nucleus to the actin cytoskeleton is highly important for actin polymerization and migration of multiple cell types as well as for mechanotransduction and even affects the cellular transcriptome.Several mechanisms of organization of actin filaments next to the nuclear envelope have been identified.Among these mechanisms the most studied one is the Linker of nucleoskeleton and cytoskeleton(LINC)complex-dependent perinuclear actin organization.However,recently additional mechanisms have been identified:an Actin-related protein-2/3(Arp2/3)-dependent perinuclear actin polymerization during migration of dendritic cells and a perinuclear actin rim that is formed in response to external force application or migration cues.In parallel,there are also reports on cancer cells that migrate in a LINC complex independent manner and on cancers with reduced expression of the LINC complex components.Thus,suggesting that LINC complex independent migration may be associated with tumour formation.展开更多
Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the mali...Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the malignant progress of gliomas. By virtue of integrated proteomics and genomics analyses as well as experimental validations, we identify three nuclear lamin genes(LMNA, LMNB1, and LMNB2) that are significantly upregulated in glioma tissues compared with normal brain tissues. We show that elevated expressions of LMNB1, LMNB2, and LMNA in glioma cells are highly associated with the rapid progression of the disease and the knockdown of LMNB1, LMNB2, and LMNA dramatically suppresses glioma progression in both in vitro and in vivo mouse models. Moreover, the repression of glioma cell growth by lamin knockdown is mediated by the p Rb-mediated G1-S inhibition. On the contrary, overexpression of lamins in normal human astrocytes dramatically induced nuclear morphological aberrations and accelerated cell growth. Together, our multi-omics-based analysis has revealed a previously unrecognized role of lamin genes in gliomagenesis, providing a strong support for the key link between aberrant tumor nuclear shape and the survival of glioma patients. Based on these findings, lamins are proposed to be potential oncogene targets for therapeutic treatments of brain tumors.展开更多
After lamins A, B and C were isolated and purified from rat liver, their assembly properties were examined by electron microscopy and scanning tunneling microscopy using negative staining and the glycerol coating meth...After lamins A, B and C were isolated and purified from rat liver, their assembly properties were examined by electron microscopy and scanning tunneling microscopy using negative staining and the glycerol coating method,respectively By varying the assembly time or the ionic conditions under which polymerization takes place, we have observed different stages of lamin assembly, which may provide clues on the structure of the 10 nm lamin filaments. At the first level of structural organization, two lamin polypeptides associate laterally into dimers with the two domains being parallel and in register. At the second level of structural organization, two dimers associate in a half-staggered and atiparallel fashion to form a tetramer 75 nm in length. At the third level of structural organization, 4-10 lamin tetramers associate laterally in register to form 75 nm long 10nm filaments, which in turn combine head to head into long, fully assembled lamin filaments.The assembled lamin filaments are nonpolar.展开更多
文摘Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. To date, at least 9 different human diseases, which superficially seem to share little with one another, result from LMNA mutations. The position of the mutation within LMNA appears to be associated with the phenotypes. This review gives an overview of genotype-phenotype relationship and describes recent advances in animal models and pathogenic mechanisms.
文摘Cell aging,the fundamental unit of biological decay,is responsible for senile disease. With the development of research,the mechanism of cell aging has been investigated in molecular level. Two hypotheses have emerged to explain the reason that lamins contribute to cell aging,one is the mechanical stress hypothesis,the other is the gene expression hypothesis. The latter proposes that mutations in A-type lamins lead to abnormal tissue-specific gene regulation. In recent years,the molecular mechanisms of lamins causing cell aging primarily include gene mutation,Zmpste24 mutation,CAAX mutation and other mutations. These mutations in the gene that encode nuclear lamins cause nuclear lamina damage directly and result in cell aging,which have been associated with several degenerative disorders.
基金This research was funded by the Israel Cancer Association,Grant No.20190028 and Ariel University.
文摘The link of the metazoan nucleus to the actin cytoskeleton is highly important for actin polymerization and migration of multiple cell types as well as for mechanotransduction and even affects the cellular transcriptome.Several mechanisms of organization of actin filaments next to the nuclear envelope have been identified.Among these mechanisms the most studied one is the Linker of nucleoskeleton and cytoskeleton(LINC)complex-dependent perinuclear actin organization.However,recently additional mechanisms have been identified:an Actin-related protein-2/3(Arp2/3)-dependent perinuclear actin polymerization during migration of dendritic cells and a perinuclear actin rim that is formed in response to external force application or migration cues.In parallel,there are also reports on cancer cells that migrate in a LINC complex independent manner and on cancers with reduced expression of the LINC complex components.Thus,suggesting that LINC complex independent migration may be associated with tumour formation.
基金supported by grants from High-level students returning to China (team) project in Hangzhou (2017)Zhejiang Provincial Natural Science Foundation of China (LY19C090002, LQ18C090005)Hangzhou Agriculture and Social Development Project (20191203B20)。
文摘Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the malignant progress of gliomas. By virtue of integrated proteomics and genomics analyses as well as experimental validations, we identify three nuclear lamin genes(LMNA, LMNB1, and LMNB2) that are significantly upregulated in glioma tissues compared with normal brain tissues. We show that elevated expressions of LMNB1, LMNB2, and LMNA in glioma cells are highly associated with the rapid progression of the disease and the knockdown of LMNB1, LMNB2, and LMNA dramatically suppresses glioma progression in both in vitro and in vivo mouse models. Moreover, the repression of glioma cell growth by lamin knockdown is mediated by the p Rb-mediated G1-S inhibition. On the contrary, overexpression of lamins in normal human astrocytes dramatically induced nuclear morphological aberrations and accelerated cell growth. Together, our multi-omics-based analysis has revealed a previously unrecognized role of lamin genes in gliomagenesis, providing a strong support for the key link between aberrant tumor nuclear shape and the survival of glioma patients. Based on these findings, lamins are proposed to be potential oncogene targets for therapeutic treatments of brain tumors.
文摘After lamins A, B and C were isolated and purified from rat liver, their assembly properties were examined by electron microscopy and scanning tunneling microscopy using negative staining and the glycerol coating method,respectively By varying the assembly time or the ionic conditions under which polymerization takes place, we have observed different stages of lamin assembly, which may provide clues on the structure of the 10 nm lamin filaments. At the first level of structural organization, two lamin polypeptides associate laterally into dimers with the two domains being parallel and in register. At the second level of structural organization, two dimers associate in a half-staggered and atiparallel fashion to form a tetramer 75 nm in length. At the third level of structural organization, 4-10 lamin tetramers associate laterally in register to form 75 nm long 10nm filaments, which in turn combine head to head into long, fully assembled lamin filaments.The assembled lamin filaments are nonpolar.
