Biomedical subjects

B Lim

Publications and source records attributed to B Lim.

At least 19 recordsLinked to original sources

PubMed2001

Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6.

The androgen receptor (AR) is a hormone-dependent transcription factor that plays important roles in male sexual differentiation and development. Transcription activation by steroid hormone receptors, such as the androgen receptor, is mediated through interaction with cofactors. We recently identified a novel AR-interacting protein, provisionally termed PAK6, that shares a high degree of sequence similarity with p21-activated kinases (PAKs). PAK6 is a 75-kDa protein that contains a putative amino-terminal Cdc42/Rac interactive binding motif and a carboxyl-terminal kinase domain. A domain-specific and ligand-dependent interaction between AR and PAK6 was further confirmed in vivo and in vitro. Northern blot analysis revealed that PAK6 is highly expressed in testis and prostate tissues. Most importantly, immunofluorescence studies showed that PAK6 cotranslocates into the nucleus with AR in response to androgen. Transient transfection experiments showed that PAK6 specifically repressed AR-mediated transcription. This report identifies a novel function for a PAK-homologous protein and suggests a potential unique mechanism by which other signal transduction pathways may cross-talk with AR pathways to regulate AR function in normal and malignant prostate cells.

Amino Acid Sequence↗

PubMed2000

Androgen receptor interacts with a novel MYST protein, HBO1.

The androgen receptor (AR), a member of the nuclear receptor superfamily, plays a central role in male sexual differentiation and prostate cell proliferation. Results of treating prostate cancer by androgen ablation indicate that signals mediated through AR are critical for the growth of these tumors. Like other nuclear receptors, AR exerts its transcriptional function by binding to cis-elements upstream of promoters and interacting with other transcriptional factors (e.g. activators, repressors and modulators). To determine the mechanism of AR-regulated transcription, we used the yeast two-hybrid system to identify AR-associated proteins. One of the proteins we identified is identical to the human origin recognition complex-interacting protein termed HBO1. A ligand-enhanced interaction between AR and HBO1 was further confirmed in vivo and in vitro. Immunofluorescence experiments showed that HBO1 is a nuclear protein, and Northern blot analysis revealed that it is ubiquitously expressed, with the highest levels present in human testis. HBO1 belongs to the MYST family, which is characterized by a highly conserved C2HC zinc finger and a putative histone acetyltransferase domain. Surprisingly, two yeast members of the MYST family, SAS2 and SAS3, have been shown to function as transcription silencers, despite the presence of the histone acetyltransferase domain. Using a GAL4 DNA-binding domain assay, we mapped a transcriptional repression domain within the N-terminal region of HBO1. Transient transfection experiments revealed that HBO1 specifically repressed AR-mediated transcription in both CV-1 and PC-3 cells. These results indicate that HBO1 is a new AR-interacting protein capable of modulating AR activity. It could play a significant role in regulating AR-dependent genes in normal and prostate cancer cells.

Acetyltransferases↗

PubMed1999

On the relation between aggregation, packing and the backscattered ultrasound signal for whole blood.

Previous studies have shown that the backscattered ultrasound (US) power from blood depends on the manner in which red blood cells (RBCs) are packed and, in particular, on spatial variations in the red blood cell number density (i.e., the RBC concentration variance). Experimental measurements have also shown that the backscattered US power depends on the degree of RBC aggregation, and it has been hypothesized that this is primarily due to the effect of RBC aggregation on the concentration variance. An initial simulation study of the relationship between RBC aggregation and packing statistics is presented, in which the effects of hematocrit, aggregate size, shape and size distribution on concentration variance are investigated. Both two-dimensional (2-D) and 3-D samples of aggregated and disaggregated RBCs were simulated; these enabled the concentration variance to be calculated. In agreement with theoretical predictions and experimental US results, the concentration variance for disaggregated RBCs is shown to be lowest at low and high hematocrits, and to peak at intermediate hematocrits. The concentration variance is shown to be particularly sensitive to changes in aggregate size and size distribution, and less sensitive to the shape of small aggregates. The results of this study provide a foundation for relating the state of aggregation in a blood sample to the manner in which RBCs are packed and, therefore, to the backscattered US power.

Blood Flow Velocity↗

PubMed1999

Effect of FK 506 on the cornea: use of topical FK 506 in corneal transplantation in a guinea pig-rat model.

To evaluate the effect of different concentrations 0.03%, 0.1% and 0.3% of FK 506 on xenograft corneal rejection, guinea pig corneas were transplanted into rats. FK 506 was then applied topically four times a day for 21 days. The grafts were inspected and scored according to opacity, edema, and graft protrusion. All grafts in the control group were rejected by the 14th postoperative day, and grafts in the FK 506 treated groups began to be rejected by the 17th postoperative day. Inflammatory cell infiltration was less dense in the FK 506 treated grafts than in the control group. Higher concentrations of FK 506 appeared to be more effective in preventing and decreasing the severity of the graft rejection. Topical FK 506 can delay the development of xenograft corneal rejection and decrease its severity in this animal model.

Administration, Topical↗

PubMed1998

Human ARHGDIG, a GDP-dissociation inhibitor for Rho proteins: genomic structure, sequence, expression analysis, and mapping to chromosome 16p13.3.

GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activity of GTPases. We recently reported the identification of a new GDI for the Rho-related GTPases named RhoGDIgamma. This gene is now designated ARHGDIG by HUGO. Here, in a detailed analysis of tissue expression of ARHGDIG, we observe high levels in the entire brain, with regional variations. The mRNA is also present at high levels in kidney and pancreas and at moderate levels in spinal cord, stomach, and pituitary gland. In other tissues examined, the mRNA levels are very low (lung, trachea, small intestine, colon, placenta) or undetectable. RT-PCR analysis of total RNA isolated from exocrine pancreas and islets shows that the gene is expressed in both tissues. We also report the genomic structure of ARHGDIG. The gene spans over 4 kb and is organized into six exons and five introns. The upstream region lacks a canonical TATA box and contains several putative binding sites for ubiquitous and tissue-specific factors active in central nervous system development. Using FISH, we have mapped the gene to chromosome band 16p13.3. This band is rich in deletion mutants of genes involved in several human diseases, notably polycystic kidney disease, alpha-thalassemia, tuberous sclerosis, mental retardation, and cancer. The promoter structure and the chromosomal location of RhoGDIgamma suggest its importance and underscore the need for further investigation into its biology.

Base Sequence↗

PubMed1998

cDNA cloning and functional characterization of the mouse Ca2+-gated K+ channel, mIK1. Roles in regulatory volume decrease and erythroid differentiation.

We have cloned from murine erythroleukemia (MEL) cells, thymus, and stomach the cDNA encoding the Ca2+-gated K+ (KCa) channel, mIK1, the mouse homolog of hIK1 (Ishii, T. M., Silvia, C., Hirschberg, B., Bond, C. T., Adelman, J. P., and Maylie, J. (1997) Proc. Natl. Acad. Sci.(U. S. A. 94, 11651-11656). mIK1 mRNA was detected at varied levels in many tissue types. mIK1 KCa channel activity expressed in Xenopus oocytes closely resembled the Kca of red cells (Gardos channel) and MEL cells in its single channel conductance, lack of voltage-sensitivity of activation, inward rectification, and Ca2+ concentration dependence. mIK1 also resembled the erythroid channel in its pharmacological properties, mediating whole cell and unitary currents sensitive to low nM concentrations of both clotrimazole (CLT) and its des-imidazolyl metabolite, 2-chlorophenyl-bisphenyl-methanol, and to low nM concentrations of iodocharybdotoxin. Whereas control oocytes subjected to hypotonic swelling remained swollen, mIK1 expression conferred on oocytes a novel, Ca2+-dependent, CLT-sensitive regulatory volume decrease response. Hypotonic swelling of voltage-clamped mIK1-expressing oocytes increased outward currents that were Ca2+-dependent, CLT-sensitive, and reversed near the K+ equilibrium potential. mIK1 mRNA levels in ES cells increased steadily during erythroid differentiation in culture, in contrast to other KCa mRNAs examined. Low nanomolar concentrations of CLT inhibited proliferation and erythroid differentiation of peripheral blood stem cells in liquid culture.

Animals↗

PubMed1998

IkappaB is a substrate for a selective pathway of lysosomal proteolysis.

In lysosomes isolated from rat liver and spleen, a percentage of the intracellular inhibitor of the nuclear factor kappa B (IkappaB) can be detected in the lysosomal matrix where it is rapidly degraded. Levels of IkappaB are significantly higher in a lysosomal subpopulation that is active in the direct uptake of specific cytosolic proteins. IkappaB is directly transported into isolated lysosomes in a process that requires binding of IkappaB to the heat shock protein of 73 kDa (hsc73), the cytosolic molecular chaperone involved in this pathway, and to the lysosomal glycoprotein of 96 kDa (lgp96), the receptor protein in the lysosomal membrane. Other substrates for this degradation pathway competitively inhibit IkappaB uptake by lysosomes. Ubiquitination and phosphorylation of IkappaB are not required for its targeting to lysosomes. The lysosomal degradation of IkappaB is activated under conditions of nutrient deprivation. Thus, the half-life of a long-lived pool of IkappaB is 4.4 d in serum-supplemented Chinese hamster ovary cells but only 0.9 d in serum-deprived Chinese hamster ovary cells. This increase in IkappaB degradation can be completely blocked by lysosomal inhibitors. In Chinese hamster ovary cells exhibiting an increased activity of the hsc73-mediated lysosomal degradation pathway due to overexpression of lamp2, the human form of lgp96, the degradation of IkappaB is increased. There are both short- and long-lived pools of IkappaB, and it is the long-lived pool that is subjected to the selective lysosomal degradation pathway. In the presence of antioxidants, the half-life of the long-lived pool of IkappaB is significantly increased. Thus, the production of intracellular reactive oxygen species during serum starvation may be one of the mechanisms mediating IkappaB degradation in lysosomes. This selective pathway of lysosomal degradation of IkappaB is physiologically important since prolonged serum deprivation results in an increase in the nuclear activity of nuclear factor kappa B. In addition, the response of nuclear factor kappa B to several stimuli increases when this lysosomal pathway of proteolysis is activated.

Animals↗

PubMed1998

Activation of the c-fos serum response element by phosphatidyl inositol 3-kinase and rho pathways in HeLa cells.

Many growth factors rapidly induce transcription of the c-fos proto-oncogene. We have investigated the pathways for induction of the c-fos promoter by serum and epidermal growth factor (EGF) in HeLa cells. Induction of the serum response element (SRE) of the c-fos promoter could be split into two parts, one involving the serum response factor-associated ternary complex factor (TCF) factors and the second mediated by core SRE sequences. Serum induction was mediated primarily by the core SRE, whereas EGF used both the TCF and core SRE pathways. Using activated and inhibitory signaling proteins, we found that phosphatidyl inositol 3-kinase (PI3K) and rho family members could mediate activation by serum. Activation by PI3K was mediated by core SRE sequences and was dependent upon rac and rho, suggesting a PI3K-to-rac-to-rho pathway for core SRE activation. The PI3K target Akt was also capable of activating the SRE but functioned through the TCF pathway, suggesting that Akt does not mediate the primary PI3K pathway to the SRE and that Akt is capable of activating TCF family members. Serum and EGF induction of the core SRE was partially inhibited by rho and PI3K inhibitors. The use of these inhibitors demonstrates the complexity of signaling pathways to the SRE and suggests that serum activates rho by PI3K-dependent and -independent pathways.

3T3 Cells↗

PubMed1997

RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas.

GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activation of GTPases and may also be critical for the cellular compartmentalization of GTPases. RhoGDI and GDI/D4 are two currently known GDIs for the Rho-subfamily of GTPases. Using their cDNAs to screen a human brain cDNA library under low stringency, we have cloned a homologous cDNA preferentially expressed at high levels in brain and pancreas. The predicted protein, named RhoGDIgamma, is approximately 50% identical to GDI/D4 and RhoGDI. It binds to CDC42 and RhoA with less affinity compared with RhoGDI and does not bind with Rac1, Rac2, or Ras. RhoGDIgamma functions as a GDI for CDC42 but with approximately 20 times less efficiency than RhoGDI. Immunohistochemical studies showed a diffuse punctate distribution of the protein in the cytoplasm with concentration around the nucleus in cytoplasmic vesicles. Overexpression of the protein in baby hamster kidney cells caused the cells to round up with loss of stress fibers. A distinct hydrophobic amino terminus in RhoGDIgamma, not seen in the other two RhoGDIs, could provide a mechanism for localization of the GDI to specific membranous compartment thus determining function distinct from RhoGDI or GDI/D4. Our results provide evidence that there is a family of GDIs for the Rho-related GTPases and that they differ in binding affinity, target specificity, and tissue expression. We propose that RhoGDI be renamed RhoGDIalpha and GDID4 be renamed RhoGDIbeta. The new GDI should widen the scope of investigation of this important class of regulatory protein.

Amino Acid Sequence↗

PubMed1997

Thoracoscopic vagotomy for recurrent ulcer after previous gastric operation.

BACKGROUND: Recurrent peptic ulcer after previous gastric operation is a difficult surgical problem and abdominal re-operation is associated with significant morbidity, mortality and recurrence rate. METHODS: The authors report on five patients with recurrent ulcers who, after previous gastric operation, were treated with thoracoscopic vagotomy. RESULTS: All patients tolerated the procedure well without complications, and the median hospital stay was 5 days. Endoscopy confirmed healing of the ulcers in all patients. Pre-operative and postoperative gastric acid studies showed a significant postoperative reduction in both basal and maximal acid output (P < 0.05). In a follow-up period of 18-33 months, one patient had a recurrent ulcer presenting with bleeding. Gastric biopsy revealed presence of Helicobacter pylori and repeated gastroscopy after a course of H. pylori eradication treatment showed a healed ulcer. The other four patients were asymptomatic. CONCLUSIONS: We conclude that thoracoscopic vagotomy is a simple and safe procedure for the treatment of recurrent ulcers after previous gastric operation, but the long-term results need further assessment.

Adult↗

PubMed1997

Systemic lupus erythematosus: initial manifestations and clinical features after 10 years of disease.

We studied the initial manifestations and late features in our lupus patients. The clinical data of patients fulfilling the American College of Rheumatology criteria for systemic lupus erythematosus (SLE) were entered prospectively for newly diagnosed patients and cumulatively for those with at least 10 years of disease duration. Ninety-seven Group A (newly diagnosed; 86 females and 11 males; mean age 31 years; 83 Chinese, 11 Malays, and 3 Indians) and 58 Group B (more than 10 years disease duration; 56 females and 2 males; mean age 41 years; 50 Chinese, 5 Malays, and 3 Indians) lupus patients were studied. The commonest clinical features in Group A were: haematological (73%), arthritis (57%), malar rash (43%), renal disorder (31%) and photosensitivity (30%). Group B patients had haematological (78%), malar rash (73%), arthritis (69%), renal disorder (59%) and photosensitivity (33%). Renal disorder was significantly increased over the years (P < 0.001). Hypertension was present in 18% (Group A) and 59% (Group B) (P < 0.00001), diabetes mellitus in 5% (Group A) and 10% (Group B) (P = ns), atherosclerosis in 2% (Group A) and 7% (Group B) (P = ns). Cataract formation was not present in Group A patients but was present in 10% of Group B patients. Renal disorders and morbidity factors like hypertension and cataracts increased significantly over the years. Optimum treatment of lupus patients should therefore include close attention to these factors.

Adolescent↗

PubMed1996

Targeted disruption of guanosine diphosphate-dissociation inhibitor for Rho-related proteins, GDID4: normal hematopoietic differentiation but subtle defect in superoxide production by macrophages derived from in vitro embryonal stem cell differentiation.

The Rho subfamily of small guanosine triphosphate (GTP)-binding proteins, through their role in cytoskeletal organization, is involved in diverse cellular functions, including cell motility and morphologic changes during differentiation. Rac also has a special role in the production of superoxide, a key component in phagocytic antimicrobial function. Guanosine diphosphate (GDP)-dissociation inhibitors (GDIs) belong to one of three classes of proteins that regulate the critical cycling of GTP-binding proteins between the inactive and active states. Two homologous GDIs for the Rho subfamily have been identified. GDID4 is preferentially expressed in hematopoietic cells, while RhoGDI is ubiquitously expressed. Whether different physiologic functions are subserved by the two GDIs is unknown. We have derived embryonal stem (ES) cells with targeted disruption of both alleles of the GDID4 gene and examined hematopoiesis and phagocytic functions of macrophages derived from in vitro ES-cell differentiation. GDID4-/- ES cells develop like wild-type cells into colonies that contain heterogeneous populations of progenitor cells and differentiated erythromyeloid cells. GDID4-/- cells express no GDID4 protein, but have normal levels of RhoGDI. GDID4-/- macrophages phagocytose yeasts and antibody-opsonized erythrocytes as effectively as wild-type macrophages. However, a slight but consistent reduction in their capacity to generate superoxide was observed, which suggests new insight into the cellular role of GDID4. The minimal phenotypic effect of a loss of function of GDID4 also indicates a significant redundancy of function between GDID4 and RhoGDI. Their functional repertoire may be better revealed by a disruption of both genes. The use of hematopoietic cells derived in vitro from genotypically altered ES cells avoids the difficulties inherent in generating knockout animals and is a useful complementary approach for evaluating the gene function.

Animals↗

PubMed1996

LAPTM5: a novel lysosomal-associated multispanning membrane protein preferentially expressed in hematopoietic cells.

While a large body of knowledge about cell membrane proteins exists, much less is known about the repertoire and function of integral membrane proteins of intracellular organelles. In looking for novel classes of genes that are functionally important to hematopoietic cells, we have cloned the cDNA for a gene preferentially expressed in adult hematopoietic tissues. During embryonic development the gene is expressed in both hematopoietic and nonhematopoietic tissues. In cell lines the gene is expressed specifically in hematopoietic lineages, whereas in normal adult tissues the mRNA is preferentially detected at high levels in lymphoid and myeloid tissues. The predicted protein is a pentaspanner with no homology to known genes and conserved across evolution. Immunocytological and cell fractionation studies with a specific antibody revealed a protein localizing in lysosomes. The gene, provisionally named LAPTM5, maps to chromosome 1p34. The expression pattern of the gene together with preliminary evidence that the protein interacts with ubiquitin indicates that the protein may have a special functional role during embryogenesis and in adult hematopoietic cells.

Adult↗

PubMed1996

Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas.

Immunohistochemical (IHC) detection of p53 protein was compared with the presence of p53 gene mutation in many colorectal (n = 100), breast (n = 92), endometrial (n = 122), and gastric (n = 116) carcinomas. Two commercially available antibodies, DO7 and CM1, were used for IHC analysis of paraffin-embedded tissue sections. Screening for gene mutations in frozen and paraffin-embedded tumor samples was carried out using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). The frequency of nuclear staining with DO7 or CM1 for each tumor type, respectively, was colorectal (36%, 23%); breast (15%, 19%); endometrial (21%, 33%); and gastric (23%,-). Overall correlation between the two antibodies for nuclear staining was 90% for the 314 tumors analyzed. Cytoplasmic staining was observed with DO7 in 7% of breast and 5% of gastric carcinomas and with CM1 in 17% of breast and 54% of endometrial carcinomas. p53 gene mutation was found in 39% of colorectal, 28% of breast, 13% of endometrial, and 25% of gastric cancers. The concordance between p53 nuclear overexpression and gene mutation (both positive or both negative) was 68% for colorectal, 79% for breast, 76% for endometrial, and 73% for gastric carcinomas. This study provides further evidence that IHC detection of p53 protein accumulation does not always indicate the presence of a gene mutation and vice versa. Discordant results were observed in approximately 20% to 30% of the tumors studied, highlighting the need for careful characterization of both p53 gene and protein alterations when assessing the relationship between p53 status and tumor behavior.

Breast Neoplasms↗

PubMed1996

Particle and voxel approaches for simulating ultrasound backscattering from tissue.

In modeling the backscattering of pulsed ultrasound from tissue, variations in compressibility are frequently approximated by assuming that an appropriate distribution of particles will produce a similar signal. For high particle densities, the computational burden can be large if simulations are conducted on a sample volume of realistic size. The approximate voxel approach offers the potential for greatly reduced computational burden, especially for three-dimensional simulations. One- and two-dimensional computer simulations were performed using both approaches with a realistic wideband Gaussian-shaped transmit signal. The mean squared errors of the simulated backscattered signals were compared to determine how the accuracy of the voxel approach depended on the scatterer concentration and voxel size selection. It is shown that the voxel approach can be used in place of the particle method with a high degree of accuracy, while considerably reducing computation time.

Blood↗

PubMed1995

Early CD34high cells can be separated into KIThigh cells in which transforming growth factor-beta (TGF-beta) downmodulates c-kit and KITlow cells in which anti-TGF-beta upmodulates c-kit.

We have previously shown that early human CD34high hematopoietic progenitors are maintained quiescent in part through autocrine transforming growth factor-beta 1 (TGF-beta 1). We also demonstrated that, in the presence of interleukin-3, interleukin-6, granulocyte colony-stimulating factor, and erythropoietin, TGF-beta 1 antisense oligonucleotides or anti-TGF-beta serum have an additive effect with KIT ligand (Steel factor [SF]), which suggests that they control different pathways of regulation in these conditions. This finding also suggests that autocrine TGF-beta 1 might suppress c-kit expression in primitive human hematopoietic progenitors. We have now distinguished two subpopulations of CD34high cells. One subpopulation expresses a c-kit mRNA that can be downmodulated by exogenous TGF-beta 1 within 6 hours. Another subpopulation of early CD34high cells expresses a low or undetectable level of c-kit mRNA, but its expression can be upmodulated within 6 hours by anti-TGF-beta. These effects disappear 48 hours after induction and cannot be maintained longer than 72 hours, even if TGF-beta 1 or anti-TGF-beta serum are added every day. Similar kinetics, although delayed, are observed with KIT protein expression. On the contrary, no specific effect of TGF-beta 1 was observed on c-fms, GAPDH, and transferrin receptor gene expression in these early progenitors. These results clarify the complex interaction between TGF-beta 1 and SF in normal early hematopoietic progenitors. SF does not switch off the TGF-beta 1 inhibitory pathway. Autocrine TGF-beta 1 appears to maintain these cells in a quiescent state, suppressing cell division by downmodulating the receptor of SF, a key cytokine costimulator of early progenitors.

Antibodies, Monoclonal↗

PubMed1995

A single residue can modify target-binding affinity and activity of the functional domain of the Rho-subfamily GDP dissociation inhibitors.

The GDP dissociation inhibitors (GDIs) represent an important class of regulatory proteins for the Rho- and Rab-subtype GTP-binding proteins. As a first step toward identifying the key functional domain(s) on the Rho-subtype GDI, truncations of the amino and carboxyl termini were performed. Deletion of the final four amino acids from the carboxyl terminus of Rho GDI or the removal of 25 amino acids from the amino terminus had no significant effect on the ability of the GDI to inhibit GDP dissociation from the Rho-like protein Cdc42Hs or on its ability to release Cdc42Hs from membrane bilayers. However, the deletion of 8 amino acids from the carboxyl terminus of Rho GDI eliminated both activities. To further test the importance of the carboxyl-terminal domain of the Rho GDI molecule, chimeras were constructed between this GDI and a related protein designated LD4, which is 67% identical to Rho GDI but is less potent by a factor of 10-20 than Rho GDI in functional assays with the Cdc42Hs protein. Two sets of chimeras were constructed that together indicated that as few as 6 amino acids near the carboxyl terminus of Rho GDI could impart full GDP dissociation inhibition and membrane dissociation activities on the LD4 molecule. Further analysis of this region by site-directed mutagenesis showed that a single change at residue 174 of LD4 to the corresponding residue of Rho GDI (i.e., Asp-174-->Ile) could impart nearly full (70%) Rho GDI activity on the LD4 molecule.

Amino Acid Sequence↗

PubMed1995

Transgenic mice support replication of hepatitis delta virus RNA in multiple tissues, particularly in skeletal muscle.

Hepatitis delta virus (HDV) is hepatotropic and frequently causes fulminant hepatitis in both human and nonhuman primate hosts. To understand the molecular basis of HDV tissue tropism and the mechanism of pathogenesis, transgenic mice in which replication-competent HDV dimeric RNA is expressed under the control of either liver-specific or universal transcriptional promoters were developed. The expressed RNA replicated efficiently in the liver and several tissues of nonhepatic origin. Surprisingly, maximal replication of HDV RNA occurred in skeletal muscle and was almost 100-fold greater than in the liver. These findings suggest that the hepatotropism of HDV is most likely a receptor-mediated restriction and that muscle-specific factors may facilitate HDV RNA replication. No evidence of cytopathology was apparent in most of the tissues examined, including the liver, supporting the contention that hepatocellular disease is not mediated by direct cytopathological effects associated with HDV RNA replication and gene expression. However, mild muscle atrophy in some of the transgenic mice was noted. Delta antigen was detected in the nuclei of myocytes. Only the small form, not the large form, of delta antigen was detected, suggesting that the RNA editing event which causes the conversion of delta antigen did not occur in transgenic mice. Furthermore, the 0.8-kb antigenomic RNA species, which is postulated to be the mRNA for delta antigen, was not detected in mice. The preferential replication of HDV RNA in skeletal muscle suggests that HDV RNA replication can be facilitated by certain muscle-specific factors.

Actins↗