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J Duvall

Publications and source records attributed to J Duvall.

At least 19 recordsLinked to original sources
PubMed2000

Insights into the molecular mechanism of p53 inhibition by HTLV type 1 Tax.

The p53 protein plays a pivotal role in transmitting signals from many forms of genotoxic stress to genes and factors that control aspects of the cell cycle and death. Although mutated in approximately 60% of all human cancers, only a minority of human T-lymphotropic virus type 1 (HTLV-1)-transformed cells carry p53 mutations. Nevertheless, the p53 protein in HTLV-1-transformed cells is functionally inactive. We have previously demonstrated that the HTLV-1 Tax protein can inhibit p53 trans-activation function. Tax does not accomplish this by directly binding to p53, but rather by a unique mechanism that includes constitutive phosphorylation of p53 at Ser-15 and Ser-392. Analysis of Tax mutants in lymphocytes demonstrates that Tax-induced p53 inhibition correlates with the ability of Tax to activate NF-kappaB, but not p300 binding or CREB trans-activation. Consistent with these results, expression of the I-kappaBalpha(S32,36A) mutant that blocks NF-kappaB activation blocks Tax-mediated p53 inhibition. We further demonstrate the importance of Tax activation of NF-kappaB in p53 inhibition, using p65 knockout (KO) mouse embryo fibroblasts (MEFs). In the absence of p65 Tax could not inhibit p53. Tax does activate IKKbeta in the p65 KO MEFs, indicating that prenuclear events of NF-kappaB activation are not sufficient for Tax-mediated p53 inhibition, but rather NF-kappaB transcriptional activation is critical. Importantly, using phosphospecific antibodies, we demonstrate that phosphorylation of p53 at Ser-15 and Ser-392 correlates with Tax-mediated inhibition. In addition, mutation of p53 at Ser-15 and Ser-392 to alanines renders p53 resistant to Tax inhibition. This report reviews p53 inhibition by Tax and presents our current model.

Animals↗
PubMed2000

Cell cycle-regulated transcription by the human immunodeficiency virus type 1 Tat transactivator.

Cyclin-dependent kinases are required for the Tat-dependent transition from abortive to productive elongation. Further, the human immunodeficiency virus type 1 (HIV-1) Vpr protein prevents proliferation of infected cells by arresting them in the G(2) phase of the cell cycle. These findings suggest that the life cycle of the virus may be integrally related to the cell cycle. We now demonstrate by in vitro transcription analysis that Tat-dependent transcription takes place in a cell cycle-dependent manner. Remarkably, Tat activates gene expression in two distinct stages of the cell cycle. Tat-dependent long terminal repeat activation is observed in G(1). This activation is TAR dependent and requires a functional Sp1 binding site. A second phase of transactivation by Tat is observed in G(2) and is TAR independent. This later phase of transcription is enhanced by a natural cell cycle blocker of HIV-1, vpr, which arrests infected cells at the G(2)/M boundary. These studies link the HIV-1 Tat protein to cell cycle-specific biological functions.

Cell Cycle↗
PubMed2000

Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-kappaB pathway and is dependent on p53 phosphorylation.

p53 plays a key role in guarding cells against DNA damage and transformation. We previously demonstrated that the human T-cell lymphotropic virus type 1 (HTLV-1) Tax can inactivate p53 transactivation function in lymphocytes. The present study demonstrates that in T cells, Tax-induced p53 inactivation is dependent upon NF-kappaB activation. Analysis of Tax mutants demonstrated that Tax inactivation of p53 function correlates with the ability of Tax to induce NF-kappaB but not p300 binding or CREB transactivation. The Tax-induced p53 inactivation can be overcome by overexpression of a dominant IkappaB mutant. Tax-NF-kappaB-induced p53 inactivation is not due to p300 squelching, since overexpression of p300 does not recover p53 activity in the presence of Tax. Further, using wild-type and p65 knockout mouse embryo fibroblasts (MEFs), we demonstrate that the p65 subunit of NF-kappaB is critical for Tax-induced p53 inactivation. While Tax can inactivate endogenous p53 function in wild-type MEFs, it fails to inactivate p53 function in p65 knockout MEFs. Importantly, Tax-induced p53 inactivation can be restored by expression of p65 in the knockout MEFs. Finally, we present evidence that phosphorylation of serines 15 and 392 correlates with inactivation of p53 by Tax in T cells. This study provides evidence that the divergent NF-kappaB proliferative and p53 cell cycle arrest pathways may be cross-regulated at several levels, including posttranslational modification of p53.

Animals↗
PubMed1994

Transcriptional activation of minimal HIV-1 promoter by ORF-1 protein expressed from the SalI-L fragment of human herpesvirus 6.

The SalI-L fragment of human herpesvirus 6 (HHV-6) strain U1102 transformed rodent cells and transactivated the HIV-1 LTR 10- to 15-fold in both monkey fibroblasts and human T-lymphocytes. In this report, the SalI-L transactivator of the HIV-1 LTR was localized to ORF-1 which codes for a protein of 357 amino acids. To determine if ORF-1 required functional Sp1 binding sites or the TATA box element of HIV-1 LTR for transactivation, 5'-deletion mutants of the HIV-1 LTR were employed. Plasmids pBS/SalI-L, pBS/SalI-L-SH, and pC6/ORF-1(S), a mammalian expression vector containing ORF-1, all transactivated a deletion mutant of HIV-1 LTR lacking functional Sp1 binding sites (CD-54). These studies demonstrate that transactivation occurred in the absence of Sp1 binding sites and required only a minimal HIV-1 promoter which contains the TATA box element. The specificity of the SalI-L transactivator for HIV-1 LTR was demonstrated by its inability to transactivate the human papillomavirus type 16 or 18 early promoters. The ORF-1 gene was cloned into and expressed from the pET17b bacterial expression vector. Purified ORF-1 protein was obtained by ammonium sulfate precipitation, Mono-S chromatography, and anti-T7. Tag immunoaffinity chromatography. Transactivation of the HIV-1 LTR by ORF-1 protein was demonstrated by electroporation studies in vivo and by transcription studies in vitro. To substantiate the putative biological role of ORF-1, pBS/SalI-L, pBS/SalI-L-SH, and pC6/ORF-1 all reactivated tat-defective HIV-1 provirus from latently infected cells expressing CD4. Thus, the data presented suggest that HHV-6 infection could have a cofactor role in the progression of AIDS.

Amino Acid Sequence↗
PubMed1993

Adopted and biological children in the clinic: family, parental and child characteristics.

Adopted children are overrepresented in referrals to mental health facilities. Research has described child symptomatology but has rarely described family characteristics or how adoptive and biological families presenting a child for treatment differ. This study took a systemic approach carrying out a multilevel assessment of families of adopted and biological children presented for treatment with adopted and biological nonclinical comparison groups. The results from this study of 88 parents of 7-17-year-old children suggest that adoptive families have greater social and psychological resources that can be relied on in treatment. However, adopted children are perceived to have more problems and their families are more likely to consider removal of the child as a solution to problems. Therapists' failure to appreciate these unique strengths and vulnerabilities of adoptive families can lead to treatment failure.

Adolescent↗
PubMed1989

Cellular mechanisms of iris neovascularization secondary to retinal vein occlusion.

We developed an animal model that allows the early phases of iris neovascularization to be studied in detail. Three major retinal branch veins were occluded with the argon laser in five eyes of cynomolgus monkeys, after which the eyes were enucleated at various time intervals. We observed three phases of the neovascular process in the iris. The early phase was characterized by vessel dilation and intense uptake of tritiated thymidine in the vascular endothelial cells. In the intermediate phase, prominent new vessels, ectropion uveae, peripheral anterior synechiae, and elevated intraocular pressure developed. Also noted were a decrease in tritiated thymidine uptake of the endothelial cells, a remarkable increase in stromal cell tritiated thymidine activity, and the formation of a neovascular membrane in association with the anterior migration of stromal cells. The late phase was marked by a further reduction of tritiated thymidine uptake and regression of the neovascular membrane.

Animals↗
PubMed1988

Nanophthalmic sclera. Fibronectin studies.

The authors performed fibronectin studies on scleral specimens derived from a patient with nanophthalmos. Immunohistochemical staining with antifibronectin was conducted using both formaldehyde-fixed, paraffin-embedded tissue sections and unfixed tissue-cultured scleral cells. In each case, the nanophthalmic samples exhibited fibronectin staining stronger than that obtained from normal human subjects. Results from an enzyme-linked immunosorbent assay (ELISA) confirmed the histologic findings that, in tissue culture, the patient's scleral cells contained and secreted a higher amount of fibronectin than did the normal control cells. The elevated fibronectin level may be related to the development of nanophthalmos.

Adult↗
PubMed1987

Histopathologic study of ocular changes in a syndrome of multiple congenital anomalies.

We examined a 5-month-old boy who had an iris coloboma in the left eye, persistent hyaloid artery, macular hypoplasia, left aberrant nerve palsy, and bilateral blepharoptosis. He had microcephaly and bilateral corticospinal tract dysfunction. Additionally, he had brachycephaly, a high arched palate, hypospadias, a malformed left external ear, and bilateral finger contractures. Computed tomography showed agenesis of the corpus callosum. He died at age 5 months. On histologic examination the left eye showed an iris coloboma, ciliary epithelial differentiation to the retina, undifferentiated neuroepithelium beneath the equatorial retina, persistent hyaloid artery, and optic nerve coloboma and pit. These findings may result from failure of the fetal fissure of the optic cup to close, with redundant folds of neuroepithelium and focal aberrant differentiation. The constellation of developmental defects indicates that an insult occurred during the sixth week of gestation.

Abnormalities, Multiple↗
PubMed1987

Identification of p40x-responsive regulatory sequences within the human T-cell leukemia virus type I long terminal repeat.

Distinct transcriptional regulatory sequences located within the upstream sequences required for p40x trans-activation of the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) were chemically synthesized and cloned upstream of the basal HTLV-I LTR promoter. Plasmids containing a single 21-base-pair (bp) repeat were weakly inducible by p40x. The level of trans-activation by p40x was increased when two (30-fold) or three (40-fold) 21-bp repeats were present in the upstream control region. In the mutant containing two 21-bp repeats, the upstream 21-bp repeat could be positioned in either the sense (30-fold) or the antisense (16-fold) orientation. Plasmids containing a 51-bp repeat element, which included a single 21-bp repeat, were induced to levels similar to that obtained with the 21-bp repeat sequence alone. Template DNAs containing a single copy of the HTLV-I sequences between -117 and -160 were stimulated approximately 10-fold by p40x when one copy of the 21-bp element was located downstream.

Base Sequence↗
PubMed1986

Extensive subretinal pigment epithelial deposit in two brothers suffering from dominant retinitis pigmentosa. A histopathological study.

The eyes of two brothers with retinitis pigmentosa were removed after death and examined by a variety of techniques, including conventional histology, fluorescence microscopy and both scanning and transmission electron microscopy. Their condition was considered to be of an autosomal dominant type but with some atypical clinical features. The outstanding histological feature in both pairs of eyes was a predominantly acellular deposit of amorphous material situated between the retinal pigment epithelium and Bruch's membrane. This material extended from the disc to beyond the ora serrata. In some regions of the retinae of both brothers, there was a cellular infiltrate into the deposit and this included multinucleate cells. In one brother the deposit was lined externally by a fibrovascular membrane in some few locations. All retinae were degenerate, but all showed preservation of abnormally short and sparse photoreceptor cells in both the peripheral and macular areas. There was only patchy loss of the choriocapillaris, which could have been age-dependent rather than disease-dependent, and the remaining choroidal vessels were patent in all cases. The widespread distribution of the deposit is unusual and suggests that it arises from disordered metabolism of the retinal pigment epithelium. We could not determine whether it was a primary disease process or if it arose as a secondary phenomenon.

Electron Probe Microanalysis↗
PubMed1986

Nanophthalmic sclera. Morphologic and tissue culture studies.

We performed morphologic and tissue culture studies on scleral tissues obtained from a nanophthalmic patient. Seen by light and electron microscopy, collagens in these unusually thick scleral tissues were arranged in irregularly interlacing bundles. The size of the collagen fibers was more variable than that observed in the controls. These abnormal fibers appeared twisted and, in some areas, were more closely packed. In tissue culture, scleral cells derived from the nanophthalmic patient synthesized proteins and collagen at a rate similar to that of normal control cells. The level of glycosaminoglycan produced, however, was markedly reduced. The modified glycosaminoglycan metabolism in scleral cells may be related to the abnormal packing of collagen bundles, which may in turn contribute to the thickening of sclera and the formation of nanophthalmos.

Adult↗
PubMed1986

Probably Norrie's disease due to mutation. Two sporadic sibships of two males each, a necropsy of one case, and, given Norrie's disease, a calculation of the gene mutation frequency.

Two sibships, each with two affected males but no other affected family members, are described. All four patients at birth had small eyes with white masses visible behind clear lenses. Support for a diagnosis of Norrie's disease lies in the probable mental retardation and sudden death of one child and mental retardation in the other in one of the families, and strong support in the sensorineural deafness in one child in the other family. A necropsy was performed on the dead child. Both eyes showed the retinae to be totally non-attached. The optic nerves were thin. If the diagnosis is Norrie's disease (highly probable), the birth of the second affected child in each family supports the postulate of a mutation in the X chromosome of a germ cell of a maternal grandparent or an earlier maternal ancestor, no previous member of the family having been affected. That implies a 50% risk of the disease in future male siblings and a 50% risk of the carrier state in female sibs. When only one child is affected, the explanation could also be a mutation in that individual. Given Norrie's disease, we have calculated a mutation rate of 3.9 per million chromosomes in the Scottish population--remarkably similar to the mutation rates calculated for many dominant diseases. A diagnosis of autosomal recessive non-attachment of retina implies a 25% risk to later siblings.

Blindness↗
PubMed1985

Cellular mechanisms of resolution of drusen after laser coagulation. An experimental study.

Naturally occurring drusen in two eyes of a rhesus monkey resolved after the application to the retina of mild laser coagulation. Clinically, resolution took place approximately nine days following treatment. The cellular mechanism for resolution was observed by light and electron microscopy over a time period of three days to six weeks after treatment. A previously unidentified phagocytic cell, probably derived from the pericyte of the choriocapillaris, was observed to remove drusenoid material after laser photocoagulation. The cell appeared to be analogous to the mesangial cell of the renal glomerulus.

Animals↗
PubMed1982

Metastatic disease in the pituitary: clinical features.

Three cases of metastatic carcinoma to the pituitary gland presenting with local compression, causing field defects and nerve palsies are reported. The literature on secondary tumours in the pituitary is reviewed and the differentiation between benign and metastatic lesions is discussed. The importance of making the diagnosis preoperatively is emphasized.

Adenocarcinoma↗