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Biomedical subjects

L D Kerr

Publications and source records attributed to L D Kerr.

At least 55 records · Page 3Linked to original sources
PubMed1992

Signal transduction: the nuclear target.

Fos and jun heterodimers activate the transcription of genes containing an AP-1 site. The activity of Fos and Jun proteins is regulated by post-translational modification. The activity of the rel/NF-kappa family of transcriptional factors is regulated by their sequestration in the cytoplasm in association with the inhibitor protein, I kappa B. An ankyrin repeat motif in I kappa B proteins is required for their direct association with rel/NF-kappa B.

Animals↗
PubMed1992

The proto-oncogene bcl-3 encodes an I kappa B protein.

The bcl-3 gene product, overexpressed in chronic lymphocytic leukemia (CLL) patients with the translocation t(14;19), is a member of the I kappa B family. The bcl-3 protein is able to inhibit the DNA binding and trans-activation of authentic NF-kappa B heterodimers p50-p65 and p49-p65, as well as p50 and p49 homodimers. The bcl-3 protein does not inhibit either the DNA-binding activity of the Rel protein or its ability to trans-activate genes linked to the kappa B site. A human 37-kD protein (I kappa B alpha), identified previously as a member of the I kappa B family, is also unable to inhibit DNA-binding activity of the Rel protein. However, unlike bcl-3, the 37-kD (I kappa B alpha) protein has no effect on the DNA-binding activity of p50 or p49 homodimers. Two dimensional phosphotryptic peptide maps of the human bcl-3 and the human 37-kD (I kappa B alpha) proteins reveal that the phosphopeptides from the 37-kD (I kappa B alpha) protein are nested within the bcl-3 protein. Furthermore, bcl-3 antisera immunoprecipitates an in vitro-radiolabeled 37-kD (I kappa B alpha) protein. Proteins of 56 and 38 kD can be identified in HeLa cells stimulated with PMA and immunoprecipitated with bcl-3 antisera. Comparison of tryptic peptide maps of the bcl-3 protein synthesized in vitro, and p56 and p38 from HeLa cells, shows that they are all structurally related. Removal of the amino-terminal sequences of the bcl-3 protein generates a protein that inhibits the DNA binding of the p50-p65 heterodimer but, like the 37-kD (I kappa B alpha) protein, is no longer able to inhibit the binding of the p50 and p49 homodimers with kappa B DNA. We propose that the bcl-3 and 37-kD (I kappa B alpha) proteins are related and are members of the I kappa B family.

3T3 Cells↗
PubMed1992

Scleroderma in association with the use of bleomycin: a report of 3 cases.

Although an association between exposure to bleomycin and the development of scleroderma has been suspected, few cases are reported. We describe the development of cutaneous scleroderma in 3 patients coincident with the use of bleomycin in low cumulative doses of less than 100 U. Dramatic clinical improvement occurred in 2 patients treated with high dose steroids. Our series of 3 patients supports a causal connection between bleomycin and scleroderma. In light of the widespread use of bleomycin, this complication may be under-appreciated.

Adult↗
PubMed1992

The role of C-Fos in growth factor regulation of stromelysin/transin gene expression.

Expression of the rat stromelysin (transin) gene is stimulated by growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), and inhibited by transforming growth factor-beta (TGF beta). Stimulation by both EGF and PDGF requires the presence of factors that recognize the AP-1 binding site in the stromelysin promoter, but PDGF stimulation requires induction of the protooncogene c-fos, while EGF acts through a FOS-independent pathway. The FOS-independent pathway appears to involve protein kinase C (PKC), since EGF, but not PDGF, requires activated protein kinase C to stimulate stromelysin expression. TGF beta inhibition of stromelysin gene expression requires an upstream sequence, referred to as the TGF beta inhibitory element (TIE). FOS is also a part of a protein complex that binds to the TIE. The protooncogene FOS is therefore involved in both stimulation and inhibition of stromelysin gene expression.

3T3 Cells↗
PubMed1992

The absence of factor B activation products in scleroderma.

Previous investigators have reported the presence of complement activation products in scleroderma. Using an assay consisting of isoelectric focussing followed by immunofixation (IEF/IF) for alternative pathway activation product Ba, and an ELISA for C3d that we developed for evaluating lupus plasmas, we assayed 48 plasmas from patients with diffuse cutaneous scleroderma, 16 patients with the limited CREST variant, 2 patients with mixed connective tissue disease (MCTD) and 4 patients with Raynaud's disease. Ba was not detected in any patient's plasma. Only one plasma from a patient with CREST contained elevated levels of C3d. We cannot reconcile the absence of B activation products in our patients with scleroderma with the results of the previous report, and conclude that further studies are necessary.

Adult↗
PubMed1991

Myonecrosis and myofibrosis as complications of sickle cell anemia.

Painful crises in sickle cell anemia are associated with infarction and subsequent fibrosis of many different organs. Myonecrosis secondary to muscle infarction during a crisis and subsequent fibrosis are often not recognized as complications of sickle cell anemia. We describe four patients, all of whom had recurrent episodes of symmetric proximal muscle pain and swelling as prominent features of their crises. Muscle biopsies showed acute myonecrosis with a minimal inflammatory reaction as well as myofibrosis with abundant collagen deposition. Chronic sequelae consisted of muscle induration, atrophy, and contractures.

Adult↗
PubMed1991

c-rel activates but v-rel suppresses transcription from kappa B sites.

We show that the product of the protooncogene c-rel is a constituent of an NF-kappa B-like complex that binds to the kappa B site originally identified in the enhancer of immunoglobulin kappa light chain gene. c-rel protein synthesized in bacteria binds to the kappa B site in a sequence-specific manner. The rel-kappa B complex can be disrupted by incubation with anti-rel antibodies. The rel protein can form oligomers. The c-rel protein can activate transcription from promoters containing kappa B sites; v-rel, on the other hand, suppresses the transcription of genes linked to kappa B sites. Thus, v-rel may interfere with the normal transcriptional machinery of the cell by acting as a dominant negative mutant.

Amino Acid Sequence↗
PubMed1991

The rel-associated pp40 protein prevents DNA binding of Rel and NF-kappa B: relationship with I kappa B beta and regulation by phosphorylation.

The product of proto-oncogene Rel associates with a number of cellular proteins. We have studied the effect of one of them, a phosphoprotein of 40 kD (pp40), on the DNA-binding activity of the Rel protein. We demonstrate that purified pp40 not only inhibits the binding of Rel, but also NF-kappa B (p50-p65) heterocomplex to DNA. Additionally, I kappa B beta, but not I kappa B alpha, also prevented the binding of Rel to the kappa B site. I kappa B beta and pp40 are related proteins because (1) they share a number of common tryptic peptides, (2) their inhibitory effect on DNA binding can be abolished by preincubation with pp40-specific antiserum, and (3) labeled I kappa B beta can be immunoprecipitated with pp40 antibodies. pp40 is part of the Rel complex present in the cytoplasm and nuclear extracts of WEHI-231 cells. The activity of pp40 to inhibit the DNA binding of Rel and NF-kappa B is modulated by phosphorylation.

Animals↗
PubMed1991

A reexamination of the relationship between myositis and malignancy.

The association between myositis and malignancy has long been appreciated. However, several recent reviews question the validity of this connection and the utility of pursuing an extensive search for occult malignancy in myositis. We report 9 patients fulfilling diagnostic criteria for myositis seen in the past 12 years. In each, a neoplasm was uncovered only in the course of a systematic search or, when initial investigation was deferred, at a later time. Of the 9 patients, 6 had dermatomyositis, 3 polymyositis. In 3 cases, solid tumors were diagnosed concomitantly with the myositis. In the remaining 6 patients, an advanced neoplasm was detected in the course of followup. In retrospect, some of these tumors might have been detected at an earlier and perhaps more treatable stage had a more rigorous initial malignancy search been pursued. Based on this experience, it is imperative that the clinician undertake a more exhaustive search for occult malignancy in patients with myositis than is currently recommended.

Adult↗
PubMed1991

The coexistence of active classic rheumatoid arthritis and AIDS.

The lack of previous reports documenting the coexistence of active rheumatoid arthritis (RA) and acquired immunodeficiency syndrome (AIDS) despite an abundance of other HIV associated autoimmune phenomena has generated a hypothesis regarding the necessity of the T4 cell for the development or continued activity of RA. We are the first to describe a patient in whom AIDS did not induce a remission of active synovitis. This observation emphasizes the complexity of the pathogenesis of RA.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Clinical analysis of isolated angiitis of the central nervous system. A report of 11 cases.

Isolated angiitis of the central nervous system may occur more frequently, and with a more favorable outcome, than has previously been described. During the past 10 years, we diagnosed this condition in 11 patients ranging in age from 23 to 38 years whose initial presenting symptoms included severe headache, transient focal neurologic deficits, or seizures. The diagnosis was established in all cases by characteristic angiographic findings. All patients were initially treated with high-dose steroids; one patient later required the addition of an immunosuppressive agent. All patients responded initially to the steroids, and 10 were in clinical remission while receiving either a small dose of steroids or no medication after a mean follow-up of 33 months. One patient died 9 months after diagnosis, presumably of an intracerebral hemorrhage. This experience suggests that the diagnosis of isolated angiitis of the central nervous system should be considered in any young person complaining of persistent headache, transient focal neurologic deficits, or seizures. Angiography usually yields characteristic diagnostic findings. Treatment should consist of high-dose steroids, with the addition of immunosuppressive agents only in cases where steroids are ineffective.

Adult↗
PubMed1990

TGF-beta 1 inhibition of transin/stromelysin gene expression is mediated through a Fos binding sequence.

Transforming growth factor beta 1 (TGF-beta 1) inhibits the growth factor and oncogene induction of transin/stromelysin, a secreted matrix-degrading metalloprotease. We demonstrate that a 10 bp element in the transin promoter is required for the TGF-beta 1 inhibitory effects and that this sequence is conserved in the promoter regions of several other TGF-beta 1-inhibited genes. The TGF-beta 1 inhibitory element (TIE) specifically binds a nuclear protein complex from TGF-beta 1-stimulated rat fibroblasts. Interestingly, this complex contained the c-fos proto-oncogene product, Fos, and induction of Fos expression was required for the inhibitory effect of TGF-beta 1 on transin gene expression. These results suggest that TGF-beta 1 inhibition of gene expression is mediated by the binding of a Fos-containing protein complex to the TIE promoter sequences.

Animals↗
PubMed1990

Epidermal growth factor stimulation of stromelysin mRNA in rat fibroblasts requires induction of proto-oncogenes c-fos and c-jun and activation of protein kinase C.

Stromelysin (transin) is a secreted metalloprotease that is transcriptionally induced by a variety of growth factors and oncogenes. We examined the necessity of specific secondary (protein kinase C) and tertiary (c-fos and c-jun protein products) messengers in the transactivation of stromelysin gene expression by epidermal growth factor (EGF). Rat-1 fibroblasts exposed to antisense c-fos DNA or RNA demonstrated that c-fos expression was necessary for complete EGF induction of stromelysin expression. Similar results demonstrating the necessity of c-jun protein in the EGF induction of stromelysin were obtained. We also demonstrated that protein kinase C activation is required for the EGF induction of stromelysin, since phorbol ester desensitization of C kinase proteins abolished the ability of EGF to induce stromelysin mRNA, protein, and promoter activity. In reconstitution experiments, neither c-fos, c-jun, nor C kinase activation alone induced significant stromelysin expression. Overexpression of c-fos and c-jun was able to induce stromelysin to a level similar to that of the growth factor, and stimulation of protein kinase C activity augmented this induction. The data suggest that the EGF induction of stromelysin in rat fibroblasts procedes through a pathway involving c-fos, c-jun, and protein kinase C.

Animals↗
PubMed1990

HIV associated systemic necrotizing vasculitis.

The spectrum of HIV associated rheumatic syndromes continues to expand as does our experience with the disease. The following is a case of HIV associated systemic necrotizing vasculitis documented by rectal biopsy. The patient was treated successfully with corticosteroids alone, and after 9 months of followup has no evidence of progression to frank AIDS.

Adult↗
PubMed1989

Factor B activation products in patients with systemic lupus erythematosus. A marker of severe disease activity.

Complement activation patterns were determined in a group of 51 patients with systemic lupus erythematosus (SLE), and the clinical outcomes of these patients at 2 years were correlated with the complement activation patterns. Activation of the classical pathway was monitored by analysis of C4a desArg levels and total C4 levels, and activation of the alternative pathway was monitored by isoelectric focusing/immunofixation and quantitative analyses of Factor B. Activation of C3 (a general measure of complement activation) was determined by an enzyme-linked immunosorbent assay for C3d and by quantitative analysis of C3. Patients were stratified into 3 groups: those with C4 but not C3 activation; those with C4 and C3 but not Factor B activation; and those with C4, C3, and Factor B activation. At the end of 2 years, there was a statistically significant difference in the morbidity and mortality rates of the third group of SLE patients compared with those in the other 2 groups. There was also a statistically significant association between the presence of Ba and cutaneous vasculitis. Unlike the patterns seen with in vitro-activated serum or with membrane-activated plasma, the Bb activation fragment was not present in the activated plasma samples from the SLE patients. These data suggest that activation of the alternative complement pathway may be a marker for severe SLE and that the Bb fragment may be playing a role in the development of this more serious pathologic condition.

Biomarkers↗
PubMed1988

Growth factors regulate transin gene expression by c-fos-dependent and c-fos-independent pathways.

The rapid induction of the proto-oncogene c-fos by growth factors and other bioactive agents, and the recent evidence that the c-fos protein (Fos) is associated with transcriptional complexes, suggests that Fos may represent an integral part of an intracellular messenger pathway that triggers changes in gene expression and ultimately phenotypic alterations. This report examines the role of c-fos in growth factor stimulation of transin, a matrix-degrading secreted metalloproteinase. Platelet-derived growth factor (PDGF) stimulation of transin RNA was blocked by a selective reduction in Fos synthesis with antisense c-fos mRNA, whereas epidermal growth factor (EGF) stimulation of transin occurred despite an equivalent inhibition of Fos levels. The stimulatory effect of both PDGF and EGF on transin transcription involved factors recognizing the sequence TGAGTCA, which is found in the transin promoter and is reported to be a binding site for the transcriptional factor Jun/AP-1 and for associated Fos and Fos-related complexes. Thus both Fos-dependent and Fos-independent pathways exist for growth factor regulation of gene expression, and both effects may be mediated through the same cis-acting transcription element.

Animals↗
PubMed1988

Transforming growth factor beta 1 and cAMP inhibit transcription of epidermal growth factor- and oncogene-induced transin RNA.

Transin mRNA encodes a secreted metalloprotease which is transcriptionally induced in Rat-1 cells by epidermal growth factor (EGF) and a number of oncogenes. A role for transin in tumor progression is suggested by its overexpression in malignant and metastatic tumors compared to their benign counterparts. In an effort to elucidate mechanisms by which elevated transin expression may be inhibited, it has been determined that both transforming growth factor type beta 1 (TGF beta 1) and increased levels of intracellular cyclic 5'-adenosine monophosphate (cAMP) inhibit EGF and oncogene induction of transin mRNA. The inhibition of transin mRNA occurred at the level of transcription as demonstrated by nuclear run-on assays. EGF binding studies in Rat-1 cells showed no significant effect of cAMP or TGF beta 1 on EGF receptor number or affinity. We have also examined the effects of cAMP and TGF beta 1 on oncogene-induced transin using Rat-1 cells transformed by temperature-sensitive mutants of v-src and K-ras oncogenes. Both inhibitors prevented the induction of transin RNA as well as decreased the levels of transin once elevated at the permissive temperature. Despite the similarities in the actions of TGF beta 1 and cAMP on transin gene expression, TGF beta 1 treatment did not significantly elevate intracellular cAMP levels, thus making it unlikely that cAMP is a second messenger system for TGF beta 1 action. These studies suggest that the inhibitory effects of cAMP and TGF beta 1 occur by distinct pathways at the level of gene regulation.

8-Bromo Cyclic Adenosine Monophosphate↗