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PubMed1998

[Neuropathy by n-hexanes: a generalized disorder of the intermediate filaments].

BACKGROUND: Chronic inhalation of glues containing n-hexanes produces neurofilament (NF) accumulation which induces sensory-motor polyneuropathy. In vitro assays have shown this toxic substance causes intermediate filaments (IF) aggregation in non-neuronal cells. OBJECTIVE: To describe intermediate filament changes in human pathology due to n-hexanes. PATIENTS AND METHODS: Sural nerve and skin biopsy samples from 2 patients who suffered from a severe sensory-motor polyneuropathy after prolonged inhalation of glue containing n-hexane were examined with electron microscopy and vimentin and phosphorylated NF immunocytochemistry. RESULTS: Abnormal accumulations of NF and NF-immunoreactive products occurred in nerve fibers and increased numbers of fibrils were observed in endoneurial endothelial cells of the sural nerve. In addition, abnormal vimentin-immunoreactive deposition was seen in fibroblasts and capillaries of the skin. The present results suggest that high doses of n-hexane cause a diffuse IF disorder in a similar form as occurs in giant axonal neuropathy. CONCLUSION: IF aggregation can occur in non-neuronal cells in humans, as has been previously proved in in vitro experiments. The presence of IF accumulations in Schwann cells, as seen in the ultrastructural examination, together with the electrophysiological findings showing an early decrease of sensory and motor nerve conduction velocities, suggests the existence of a primary myelinic disorder associated with axonal damage.

Adhesives↗
PubMed1986

Fluorescence study of renal cell carcinoma with antibodies to renal tubular antigens, intermediate filaments, and lectins.

A fluorescence study was performed in 16 renal cell carcinomas using antibodies to renal tubular antigens (RTA), two intermediate filaments, cytokeratin and vimentin, and two lectins, soybean agglutinin (SBA) and peanut agglutinin (PNA). We observed the presence of RTA, cytokeratin, and vimentin in all of our specimens. The expression of vimentin, the cytoskeletal protein of mesenchymal cells, was considered to be very interesting feature of the tumor. Binding sites of SBA, normally present in glomeruli, proximal and distal tubules, were detectable in the neoplastic cells in only 37.5% of our specimens. PNA did not react with the tumor except for the small area of 2 specimens. Lectins may be useful for estimating the characteristics or renal cell carcinoma including its malignant potentials, and antibodies to RTA and intermediate filaments seem to be available for the diagnosis of the tumor in metastatic lesions.

Antibodies↗
PubMed1979

Coexistence of desmin and the fibroblastic intermediate filament subunit in muscle and nonmuscle cells: identification and comparative peptide analysis.

Extraction of chicken embryo fibroblasts (CEF) or baby hamster kidney (BHK) cells with 1% Triton X-100 and 0.6 M KCl leaves an insoluble cytoskeletal residue composed primarily of the 52,000 Mr subunit of intermediate filaments (F-IFP). In addition, CEF cytoskeletons exhibit a minor component with Mr of 50,000, identified as alpha-desmin, one of the two major isoelectric variants of the intermediate filament subunit from smooth muscle. BHK cytoskeletons contain the 50,000 Mr mammalian desmin variant. Cytoskeletons prepared from chicken embryonic myotubes contain F-IFP and both alpha- and beta-desmin. These data suggest that two distinct 10-nm filament subunits coexist in a single cell. One-dimensional peptide analysis of F-IFP and desmin from avian and mammalian cells reveals significant interspecies homology, as well as homology between F-IFP and desmin from the same species. Peptide analyses of 32P-labeled intermediate filament subunits suggest that there is considerable similarity in the phosphorylation sites of these proteins. These results indicate that F-IFP and desmin might be evolutionally related.

Amino Acid Sequence↗
PubMed2002

Expression of intermediate filaments and desmosomal proteins during differentiation of the human spinal cord.

Differentiation of the human spinal cord and involution of its caudal end were investigated in 4-9-week human conceptuses using immunofluorescence and electron microscopy. In the spinal cord, several types of intermediate filament proteins and desmoglein were expressed in parallel: in early stages (4 to 6 weeks), neurofilaments were expressed in low amounts only in the neuroblast processes of the marginal layer. At 6 weeks, differences in staining intensity and distribution patterns of neurofilaments became apparent between lumbar and sacrococcygeal (tail) parts of the spinal cord. Neurofilament expression increased in the mantle and marginal layers of the lumbar spinal cord coinciding with advancing neurogenesis. In contrast, neurofilament expression decreased in the sacrococcygeal spinal cord in association with regression of all tail organs. Regression was characterized by the appearance of large amounts of dead cells and macrophages. Strong vimentin expression was found in neuroepithelial (ependymal) cells and in the radial glia of the spinal cord throughout all stages examined. Coexpression of vimentin and glial fibrillary acidic protein was found only in the radial glia in the earliest developmental stage. Desmoglein was expressed in low amounts around the central canal which was probably associated with the immature junctional complexes that were present between ependymal cells. In conclusion, temporal and spatial distribution patterns of intermediate filament proteins in specific cell populations characterizes differentiation and caudal involution of the human spinal cord.

Cell Differentiation↗
PubMed1989

Desmin-containing intermediate filaments: structural analysis using monoclonal antibodies.

1. Monoclonal antibodies have been raised against N- and C-terminal desmin sequence regions. 2. The antibodies decorated desmin intermediate filaments in a helical fashion with four antibody molecules per helix turn. 3. The filaments could be decorated with both types of antibody consecutively. 4. These results support a model of intermediate filament assembly in which the tetrameric protofilaments are aligned in a staggered fashion with partial overlapping of the central rod domain regions of the desmin sequence.

Animals↗
PubMed1989

Intermediate filament expression in astrocytic neoplasms.

Immunohistochemical analysis of 30 paraffin-embedded astrocytic neoplasms was performed to correlate the expression of intermediate filament proteins with histologic subtype. Each tumor was studied with monoclonal antibodies to keratin, vimentin, desmin, 200-kd neurofilament protein, and glial fibrillary acidic protein (GFAP). Immunoreactivity with the anti-keratin monoclonal antibodies AE1 and AE3 was demonstrated in 24 cases (80%) including 4 of 6 (66%) well-differentiated astrocytomas (WDAs), 10 of 12 (83%) anaplastic astrocytomas (ANAs), and 10 of 12 (83%) glioblastomas multiforme (GBMs). These cases were further studied with the monoclonal antikeratin antibodies 34 beta E12 and 34 beta H11. Of the 24 AE1/AE3-positive cases, 14 (58%) reacted with 34 beta E12. None of the cases was reactive with 34 beta H11. Vimentin expression was demonstrated in 24 cases (80%), including 2 of 6 (33%) WDAs, 11 of 12 (92%) ANAs, and 11 of 12 (92%) GBMs. Coexpression of keratin and vimentin was observed in 20 cases (67%), including 2 of 6 WDAs, 9 of 12 (75%) ANAs, and 9 of 12 (75%) GBMs. Immunoreactivity with GFAP antibody was present in all 30 (100%) cases, but none of the tumors was reactive with antibodies to desmin or 200-kd neurofilament protein. These findings demonstrate that expression of both keratin and vimentin intermediate filaments is common in astrocytic neoplasms regardless of histologic grade.

Astrocytoma↗
PubMed2002

Real-time observation of coiled-coil domains and subunit assembly in intermediate filaments.

We have utilized electron paramagnetic resonance spectroscopy to study secondary structure, subunit interaction, and molecular orientation of vimentin molecules within intact intermediate filaments and assembly intermediates. Spectroscopy data prove alpha-helical coiled-coil structures at individual amino acids 316-336 located in rod 2B. Analysis of positions 305, 309, and 312 identify this region as conforming to the helical pattern identified within 316-336 and thus demonstrates that, contrary to some previous predictions, this region is in an alpha-helical conformation. We show that by varying the position of the spin label, we can identify both intra- and inter-dimer interactions. With a label attached to the outside of the alpha-helix, we have been able to measure interactions between positions 348 of separate dimers as they align together in intact filaments, identifying the exact point of overlap. By mixing different spin-labeled proteins, we demonstrate that the interaction at position 348 is the result of an anti-parallel arrangement of dimers. This approach provides high resolution structural information (<2 nm resolution), can be used to identify molecular arrangements between subunits in an intact intermediate filament, and should be applicable to other noncrystallizable filamentous systems as well as to the study of protein fibrils.

Amino Acid Sequence↗
PubMed1994

Charge interactions in the rod domain drive formation of tetramers during intermediate filament assembly.

The purpose of this study was to test a long standing hypothesis regarding the forces that drive the assembly of intermediate filaments (IFs). The initial step of IF assembly is the formation of dimeric, alpha-helical coiled coils. On the outside of the coiled coils, charged amino acids are distributed periodically such that positively and negatively charged residues are arranged in alternating zones, 9.5/2 residues wide (Parry et al., 1977; McLachlan and Stewart, 1982). This structural feature has given rise to the hypothesis that, if neighboring coiled coils were staggered axially by an odd multiple of a charged zone, electrostatic interactions between them could provide the driving force for the assembly of higher order oligomers or filaments (Fraser et al., 1986; Parry and Steinert, 1992). Using the IF protein vimentin as a model system, we carried out deletion mutagenesis experiments to test this hypothesis. We generated mutant vimentin proteins lacking 14, 21, and 28 residues in Helix 1B of the rod domain, and analyzed their assembly properties by DNA transfection into IF null cells, in vitro assembly, and chemical cross-linking. Results from these experiments are consistent with, and support, the hypothesis that charge complementation plays a key role in the assembly and stabilization of intermediate filaments.

Animals↗
PubMed1985

Cellular differentiation in ovarian sex-cord-stromal and germ-cell tumors studied with antibodies to intermediate-filament proteins.

Seventy ovarian sex-cord-stromal and germ-cell tumors were immunohistochemically studied for the presence of intermediate-filament proteins of different types used as markers for cellular differentiation. Cells of ovarian granulosa-cell tumors constantly expressed vimentin and appeared to lack cytokeratin. Two tumors previously classified as granulosa-cell tumors were reclassified as poorly differentiated "common" epithelial tumors based on their cytokeratin positivity, vimentin negativity, and morphologic features. Dysgerminomas and Leydig-cell tumors showed only vimentin positivity. Tubular structures in androblastomas, which are considered to represent Sertoli-cell differentiation, were cytokeratin positive, and thus differed from the majority of normal Sertoli cells that are known to express vimentin and not cytokeratin. Embryonal carcinomas, choriocarcinomas, and endodermal sinus tumors showed cytokeratin positivity in the neoplastic cells whereas vimentin was observed in the stromal cells. In immature teratomas, epithelial differentiation was demonstrated with cytokeratin antibodies, and neural and glial differentiation was also frequently demonstrated by immunostaining with antibodies to neurofilaments and glial fibrillary acidic protein. The results show that antibodies to intermediate filaments can be used in the differential diagnosis between ovarian epithelial and nonepithelial tumors, and they provide a very accurate additional method to characterize the cellular differentiation of ovarian neoplasms.

Animals↗
PubMed1995

The neuronal intermediate filament, alpha-internexin is transiently expressed in amacrine cells in the developing mouse retina.

We have investigated the expression of intermediate filament proteins in the developing mouse retina by immunohistochemistry. Antibodies against alpha-internexin, the three neurofilament subunits (NF-L, NF-M, NF-H), vimentin, and glial fibrillary acidic protein (GFAP) were used to determine the relative expression of these proteins at different post-natal stages of mouse retinal development. alpha-Internexin is widely distributed in the process of amacrine cells, horizontal cells and retinal ganglion cells before post-natal day 5 (P5). At this age, NF-L and NF-M are detected primarily in the processes of horizontal cells and retinal ganglion cells, but are rarely found in amacrine cell processes. After P5, alpha-internexin is found to colocalize with other neuronal intermediate filaments in the cell processes of horizontal and ganglion cells, but its expression is barely detectable in amacrine cells processes. NF-H is not encountered in either the horizontal cell processes or the ganglion nerve fibers until P5. Vimentin is present in all glial cells (astrocytes and Müller cells) and some horizontal cell processes during development, while GFAP is found only in astrocyte processes of the mature retina. The transient presence of alpha-internexin in amacrine cells only in early development suggests that the protein may play a role in the plasticity of neuronal connections in the retina.

Animals↗
PubMed1984

Specific attachment of morphologically-distinct intermediate filaments to desmosomes and hemidesmosomes in the epidermis of the tadpole of the anuran, Pseudis paradoxus.

Polarization microscopy disclosed the presence of strongly birefringent intracellular structures in the basal cells of the epidermis of the tadpole of the anuran Pseudis paradoxus. The electron microscopic picture of the birefringent structures showed that they were composed of thick intermediate filaments (average diameter: 11.2 +/- 0.8 nm) oriented in a parallel disposition to form closely packed bundles which attached to the hemidesmosomes present on the basal surface of the cells of the basal layer of the epidermis. Thinner intermediate filaments (average diameter: 8.2 +/- 0.8 nm) were localized to the cortical zone of the cytoplasm; these thinner intermediate filaments converged upon the sites of cell-to-cell adhesion (desmosomes).

Animals↗
PubMed1990

[Distribution of intermediate filaments in the salivary glands and salivary gland tumors].

13 cases of salivary glands and 30 of salivary gland tumors were studied by ABC method with 6 monoclonal antibodies to intermediate filaments and one to microfilament. The results showed that the distribution of intermediate filaments in salivary glands had their regularity. According to the reaction to the antibodies, these tumors could be divided into 3 groups and 3 subgroups. The findings also suggested that in the salivary gland tissue the epithelial cells which mainly contained the 54 Kd keratin and the epithelial cells which mainly contained 57/66 Kd keratin were the origin of the salivary gland tumors. The actin-positive myoepithelial cells might play a role in some tumor formation.

Actins↗
PubMed1996

Multiple drug resistance and intermediate filaments.

One major obstacle to the successful treatment of epithelial derived tumors, such as breast and prostate carcinoma, is the presence of a multiple drug resistance phenotype. The drug resistance which is observed in growing epithelial derived cancer cells could either be an intrinsic, selected and/or an acquired characteristic. A survey of the survival data from several laboratories suggests that epithelial derived tumor cells, which have never been challenged with damaging agents, are in some cases 10 to 2,000 times more resistant to various chemotherapeutic agents as compared to hematopoietic cell lines. An intrinsic characteristic of epithelial cells is their resistance to the lethal effects of multiple types of damaging agents. A major feature of epithelial derived tumors is the expression of the intermediate filament type proteins known as cytokeratin. The simplest cytokeratin combination, cytokeratin 8 and 18, is a major cytoplasmic element within the cells of epithelial derived tumors. Earlier work showed that cytokeratin could be modified by mitoxantrone, a chemotherapeutic agent used in the treatment of breast cancer. Increasing data indicates that the intrinsic drug resistance phenotype is due in part to the presence of continued expression of the cytokeratin 8 and 18. The cytokeratin dependent drug resistance (C-MDR) has been observed in two different cell types that were engineered to contain cytokeratin 8 and 18 expression. The cytokeratin monomers are known to self assemble into intermediate filament networks as shown by numerous basic studies. Experiments using transfected cell lines which are unable to assemble networks indicated that C-MDR does not depend upon the formation of an intermediate filament network. Selection of cytokeratin network defective tumor cells did not increase their sensitivity to chemotherapeutic agents. These data are interesting since it suggests that the C-MDR phenotype is not dependent upon the structural nature (i.e. network forming ability) of the cytokeratin. Our current working hypothesis is that the interaction of the damaging agent with cytokeratin may initiate signaling response(s) for cell survival.

Animals↗
PubMedDate not supplied

Coexpression of intermediate filaments in normal and neoplastic human tissues: a reappraisal.

The current view that coexpression of intermediate filaments (IFs) must be considered a bizarre and unpredictable phenomenon, which seriously jeopardizes the use of their localization in diagnostic applications, is critically reviewed in light of the evidence so far acquired by investigations in vivo and in vitro. A less dogmatic approach, which considers IF expression the result of a series of interactions between cells and their microenvironment instead of a function of their histogenesis, not only justifies the complex variety of coexpressions observed in normal and neoplastic tissues but also confirms the usefulness of IF expression in diagnostic applications and offers new opportunities for investigations, with special regard to immunoelectron microscopy.

Cytoskeleton↗
PubMed2004

Intermediate filaments: molecular structure, assembly mechanism, and integration into functionally distinct intracellular Scaffolds.

The superfamily of intermediate filament (IF) proteins contains at least 65 distinct proteins in man, which all assemble into approximately 10 nm wide filaments and are principal structural elements both in the nucleus and the cytoplasm with essential scaffolding functions in metazoan cells. At present, we have only circumstantial evidence of how the highly divergent primary sequences of IF proteins lead to the formation of seemingly similar polymers and how this correlates with their function in individual cells and tissues. Point mutations in IF proteins, particularly in lamins, have been demonstrated to lead to severe, inheritable multi-systemic diseases, thus underlining their importance at several functional levels. Recent structural work has now begun to shed some light onto the complex fine tuning of structure and function in these fibrous, coiled coil forming multidomain proteins and their contribution to cellular physiology and gene regulation.

Amino Acid Sequence↗
PubMed2004

Immunohistochemical study of intermediate filaments and neuroendocrine marker expression in leydig cells of laboratory rodents.

The aims of this study were to detect the expression of intermediate filaments and to verify the existence of marker substances for neuronal and neuroendocrine cells within the interstitial Leydig cells of laboratory rodent's testes, such as it has been described in other species. Adult male rats, mice, gerbils, Syrian hamsters and guinea-pigs were used and the localization of the different markers was achieved by the streptoavidin-peroxidase immunohistochemical method. The present study demonstrates in all rodents studied a similar pattern of localization in Leydig cells of intermediate filaments (vimentin, cytokeratin, neurofilament 200 kD and glial fibrillary acidic protein) and other marker substances (S-100, CgA, substance P and neurone-specific enolase), which are typical of neuroendocrine (APUD cells or paraneurones) and glial cells. The expression of these substances, related to neurotransmitters or neurohomones and other proteins characteristic of neuroendocrine cells, could suggest that it is a neural crest derived cell. Although this study provides more evidences about the immunoexpression of neuronal and glial markers in Leydig cells, this fact cannot be related directly to their embryological origin, because the current data support the hypothesis of a mesenchymal origin of the Leydig cells.

Animals↗
PubMed2003

An intact intermediate filament network is required for collateral sprouting of small diameter nerve fibers.

Expression of the intermediate filament (IF) protein peripherin is initiated during development at the time of axonal extension and increases during regeneration of nerve fibers. To test whether the IF network is essential for neuron process outgrowth in the mature organism in vivo, we disrupted endogenous peripherin IF in small-sized dorsal root ganglion (DRG) neurons in transgenic mice via expression of a mutant peripherin transgene under control of peripherin gene regulatory sequences. Anatomical and functional analyses showed that these neurons send peripheral and central axonal projections to correct targets, express correct neuropeptides, and mediate acute pain responses normally. However, disruption of IF significantly impaired the ability of uninjured small-sized DRG neurons to sprout collateral axons into adjacent denervated skin, indicating a critical role for intact IF in plasticity, specifically in compensatory nociceptive nerve sprouting.

Animals↗
PubMed1986

Intermediate filament heterogeneity in normal and hypercholesterolemic rabbit vascular smooth muscle cells.

We have examined the intermediate filament (IF) protein content of vascular smooth muscle (SM) cells from several arteries and veins in rabbits and quantitated the changes which occur in SM cell expression of these proteins in response to cholesterol feeding. Cells from control rabbit arteries expressed 30% of their IF protein as desmin, while veins expressed 50% as desmin. During development of diet-induced atherosclerosis, morphological changes in arterial SM cells in the intima correlate with changes in IF expression. There is a significant increase in total IF protein content, vimentin increased differentially in thoracic aorta and desmin in pulmonary artery. In abdominal aorta both increase equally. Cholesterol feeding also resulted in changes in the expression of subspecies of desmin, vimentin, and actin in the thoracic arch. Although cholesterol feeding did not produce obvious morphological changes in the veins examined, venous SM IF protein expression was also altered. In the vena cava of cholesterol-fed rabbits there was an increase in vimentin expression without the parallel increase in desmin that occurred in the arterial system. These studies show that cholesterol feeding of rabbits induces measurable changes in the amounts of IF proteins in both arterial atherosclerotic lesions and venous SM cells.

Actins↗