The main functions of lamins are their mechanical and structural roles as major building blocks of the karyoskeleton. They are also involved in chromatin structure regulation, gene expression, intracellular signalling pathway modulation and development. All essential lamin functions seem to depend on their capacity for assembly or disassembly after the receipt of specific signals, and after specific, selective and precisely regulated interactions through their various domains. Reversible phosphorylation of lamins is crucial for their functions, so it is important to understand how lamin polymerization and interactions are modulated, and which sequences may undergo such modifications. This review combines experimental data with results of our in silico analyses focused on lamin phosphorylation in model organisms to show the presence of evolutionarily conserved sequences and to indicate specific in vivo phosphorylations that affect particular functions.

BackgroundMaspin, which is classified as a tumor suppressor protein, is downregulated in many types of cancer. Several studies have suggested potential anti-proliferative activity of maspin as well as sensitizing activity of maspin for therapeutic cytotoxic agents in breast cancer tissue culture and animal models. All of the experimental data gathered so far have been based on studies with maspin localized cytoplasmically, while maspin in breast cancer tumor cells may be located in the cytoplasm, nucleus or both. In this study, the effect of maspin cytoplasmic and nuclear location and expression level on breast cancer proliferation and patient survival was studied.MethodsTissue sections from 166 patients with invasive ductal breast cancer were stained by immunohistochemistry for maspin and Ki-67 protein. The localization and expression level of maspin were correlated with estimated patient overall survival and percent of Ki-67-positive cells. In further studies, we created constructs for transient transfection of maspin into breast cancer cells with targeted cytoplasmic and nuclear location. We analyzed the effect of maspin location in normal epithelial cell line MCF10A and three breast cancer cell lines - MCF-7, MDA-MB-231 and SKBR-3 - by immunofluorescence and proliferation assay.ResultsWe observed a strong positive correlation between moderate and high nuclear maspin level and survival of patients. Moreover, a statistically significant negative relationship was observed between nuclear maspin and Ki-67 expression in patients with invasive ductal breast cancer. Spearman’s correlation analysis showed a negative correlation between level of maspin localized in nucleus and percentage of Ki-67 positive cells. No such differences were observed in cells with cytoplasmic maspin. We found a strong correlation between nuclear maspin and loss of Ki-67 protein in breast cancer cell lines, while there was no effect in normal epithelial cells from breast. The anti-proliferative effect of nuclear maspin on breast cancer cells was statistically significant in comparison to cytoplasmic maspin.ConclusionsOur results suggest that nuclear maspin localization may be a prognostic factor in breast cancer and may have a strong therapeutic potential in gene therapy. Moreover, these data provide a new insight into the role of cytoplasmic and nuclear fractions of maspin in breast cancer.

Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.

LMNA gene encodes for nuclear intermediate filament proteins lamin A/C. Mutations in this gene lead to a spectrum of genetic disorders, collectively referred to as laminopathies. Lamin A/C are widely expressed in most differentiated somatic cells but not in early embryos and some undifferentiated cells. To investigate the role of lamin A/C in cell phenotype maintenance and differentiation, which could be a determinant of the pathogenesis of laminopathies, we examined the role played by exogenous lamin A and its mutants in differentiated cell lines (HeLa, NHDF) and less-differentiated HEK 293 cells. We introduced exogenous wild-type and mutated (H222P, L263P, E358K D446V, and ∆50) lamin A into different cell types and analyzed proteins’ impact on proliferation, protein mobility, and endogenous nuclear envelope protein distribution. The mutants give rise to a broad spectrum of nuclear phenotypes and relocate lamin C. The mutations ∆50 and D446V enhance proliferation in comparison to wild-type lamin A and control cells, but no changes in exogenous protein mobility measured by FRAP were observed. Interestingly, although transcripts for lamins A and C are at similar level in HEK 293 cells, only lamin C protein is detected in western blots. Also, exogenous lamin A and its mutants, when expressed in HEK 293 cells underwent posttranscriptional processing. Overall, our results provide new insight into the maintenance of lamin A in less-differentiated cells. Embryonic cells are very sensitive to lamin A imbalance, and its upregulation disturbs lamin C, which may influence gene expression and many regulatory pathways.Electronic supplementary materialThe online version of this article (doi:10.1007/s00412-016-0610-9) contains supplementary material, which is available to authorized users.

Lamin proteins are type V intermediate filament proteins (IFs) located inside the cell nucleus. They are evolutionarily conserved and have similar domain organization and properties to cytoplasmic IFs. Lamins provide a skeletal network for chromatin, the nuclear envelope, nuclear pore complexes and the entire nucleus. They are also responsible for proper connections between the karyoskeleton and structural elements in the cytoplasm: actin and the microtubule and cytoplasmic IF networks. Lamins affect transcription and splicing either directly or indirectly. Translocation of active genes into the close proximity of nuclear lamina is thought to result in their transcriptional silencing. Mutations in genes coding for lamins and interacting proteins in humans result in various genetic disorders, called laminopathies. Human genes coding for A-type lamin (LMNA) are the most frequently mutated. The resulting phenotypes include muscle, cardiac, neuronal, lipodystrophic and metabolic pathologies, early aging phenotypes, and combined complex phenotypes. The Drosophila melanogaster genome codes for lamin B-type (lamin Dm), lamin A-type (lamin C), and for LEM-domain proteins, BAF, LINC-complex proteins and all typical nuclear proteins. The fruit fly system is simpler than the vertebrate one since in flies there is only single lamin B-type and single lamin A-type protein, as opposed to the complex system of B- and A-type lamins in Danio, Xenopus and Mus musculus. This offers a unique opportunity to study laminopathies. Applying genetic tools based on Gal4 and in vitro nuclear assembly system to the fruit fly model may successfully advance knowledge of laminopathies. Here, we review studies of the laminopathies in the fly model system.Electronic supplementary materialThe online version of this article (10.1186/s11658-018-0093-1) contains supplementary material, which is available to authorized users.