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Biomedical subjects

D R Lowy

Publications and source records attributed to D R Lowy.

At least 127 records · Page 7Linked to original sources
PubMed1985

X-linked inheritance of epidermodysplasia verruciformis. Genetic and virologic studies of a kindred.

We describe a family with typical epidermodysplasia verruciformis (EV) in which only male members are affected. Whereas none of the index patient's ten children have EV, four of eight grandsons born to his daughters have inherited the disorder. All are infected with human papillomavirus (HPV) 3 and HPV 8. The inheritance in this kindred most likely results from an X-linked recessive genetic defect. Since other kindreds have been described with autosomal inheritance, this novel inheritance pattern suggests that the persistent high clinical susceptibility to HPV infection characteristic of EV may result from defects in either of at least two different genetic loci, one of which may be located on the X chromosome.

Animals↗
PubMed1985

Harvey ras induction of metastatic potential depends upon oncogene activation and the type of recipient cell.

NIH-3T3 cells and early passage fibroblasts transformed by various members of the rasH gene family were found to express metastatic potential in nude (Nu/Nu) mice. NIH-3T3 cells transformed by either the cloned DNA of the Harvey sarcoma virus or by the T24 human rasH oncogene were both tumorigenic after subcutaneous injection and metastatic after intravenous injection. In contrast, NIH-3T3 cells transformed by elevated levels of the proto-oncogene were tumorigenic but not metastatic. Tumor growth potential by itself, therefore, was not sufficient to induce metastatic behavior. Diploid fibroblasts transformed with the T24 rasH oncogene were tumorigenic and metastatic after intravenous injection and also produced extensive spontaneous metastases. Thus, induction of the complete metastatic phenotype by the T24 rasH oncogene does not require the use of aneuploid recipient cells such as NIH-3T3 cells. An alternative murine recipient cell type C127, when transformed by the cloned DNA of the Harvey sarcoma virus, was tumorigenic but not metastatic. The transformed C127 cells made less of the viral gene product P21 than the NIH-3T3 rasH transformants. To ensure that the decreased levels of P21 were not responsible for the lack of metastatic potential, C127 cells were transformed with altered constructs of the plasmid containing the Harvey sarcoma virus which elicited enhanced levels of P21. The augmented P21 levels, although equivalent to or greater than that seen in the NIH-3T3 transformants, did not confer metastatic potential on the C127 transformants. These results indicate that at least two complementation groups may be required for induction of metastatic capacity in this system, one involving the "activated" oncogenic form of the rasH gene and the second another as yet undefined factor in the cellular background present in NIH-3T3 cells but absent in C127 cells.

Animals↗
PubMed1984

Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus.

Previous studies of premature chain termination mutants and in frame deletion mutants of the p21 ras transforming protein encoded by the transforming gene of Harvey murine sarcoma virus (Ha-MuSV) have suggested that the C terminus is required for cellular transformation, lipid binding, and membrane localization. We have now further characterized the post-translational processing of these mutants and have also studied two C-terminal v-rasH point mutants: one encodes serine in place of cysteine-186, the other threonine for valine-187. The Thr-187 mutant was transformation-competent, and its p21 protein was processed normally, as was the p21 encoded by a transformation-competent deletion mutant from which amino acids 166-175 had been deleted. The Ser-186 mutant was defective for transformation. The p21s encoded by the Ser-186 mutant and by the previously described transformation-defective mutants did not undergo the posttranslational processing common to biologically active ras proteins: their electrophoretic migration rate did not change, they remained in the cytosol, and they failed to bind lipid. Since the cell-encoded ras proteins also contain this cysteine, we conclude that this amino acid residue is required for all ras proteins.

Animals↗
PubMed1984

Response of warts in epidermodysplasia verruciformis to treatment with systemic and intralesional alpha interferon.

The susceptibility of human papillomavirus infection to polyclonal human leukocyte interferon (IFN-alpha) has been evaluated in patients with epidermodysplasia verruciformis (EV), a disease with extensive chronic papillomavirus-induced warts. In a double-blind, placebo-controlled study with intralesional IFN-alpha, four of five IFN-alpha-treated warts regressed; none of the placebo-treated warts responded (p = 0.024). Three patients with EV were treated with systemic IFN-alpha for 4 weeks in an open study, achieving partial regression of warts in all three. In a double-blind, placebo-controlled study, warts in two children with EV regressed with systemic IFN-alpha while two who received placebo showed no improvement. The lesions recurred following cessation of therapy. At the completion of therapy with IFN-alpha, histologic normalization was accompanied by a 95% decrease in the number of viral antigen-containing cells in the warts (p less than 0.001). We conclude that warts in EV respond to systemic and intralesional IFN-alpha.

Adult↗
PubMed1984

Tumor viruses, oncogenes, and human cancer.

We review the biology of transforming retroviruses and their relationship to cellular transforming genes (tumor oncogenes). Evidence is discussed for the involvement of a retrovirus in a newly described syndrome, "adult T cell leukemia/lymphoma," which has a high incidence of skin involvement. This virus is related to the animal retroviruses which induce tumors in susceptible hosts after a long latent period. Cellular transforming genes encode proteins which directly change the oncogenic potential of a cell. These genes, which are altered forms of normal cellular genes, have been isolated from a wide variety of human tumors. Viral and cellular transforming genes produce their changes by at least two different mechanisms: abnormally high production of the normal protein encoded by these genes, or normal levels of an altered form of the protein.

Animals↗
PubMed1984

Identification of a second transforming region in bovine papillomavirus DNA.

Bovine papillomavirus type 1 (BPV-1) has been used as a model for studying papillomavirus genetics because BPV-1 virions or BPV-1 genomic viral DNA efficiently induce morphologic transformation of certain cultured cells. Previous studies of BPV-1-induced transformation have found that a cloned 5.4-kilobase (kb) fragment (69T) of the genome is transforming and that a 2.3-kb segment from the 3' end of this fragment is also transforming if activated by a retroviral regulatory element (the long terminal repeat). We now report that 69T contains another transforming segment near its 5' end that can also be activated by a long terminal repeat. Since this second segment does not overlap the 3' transforming segment, we conclude that BPV-1 encodes at least two genes that can independently transform cultured cells. Mutational analysis of the 5' transforming segment suggests that the transforming gene of this segment lies within the E6 open reading frame. The two transforming segments differ in their biological activity in that the E6-containing fragment can transform C127 mouse cells but not NIH3T3 mouse cells, whereas the 3' fragment can transform both cell lines.

Animals↗
PubMed1984

In vitro transformation by bovine papillomavirus.

We have studied tumorigenic transformation of mouse tissue culture cells by bovine papillomavirus (BPV) as a model of papillomavirus-induced cell proliferation. When BPV or its 7.9-kb full-length viral DNA genome induces focal transformation of mouse calls, the viral DNA is maintained in the transformed cells as multiple extrachromosomal copies. The transforming capacity was initially localized to a 69% subgenomic fragment of the viral DNA genome. We have further characterized the BPV DNA sequences that can encode the transforming function by generating and analyzing the transforming activity of a series of BPV DNA deletion mutants. The results indicated that two discontinuous segments of the viral DNA are required for transformation. One segment, near the 5' end of the 69% transforming fragment, probably represents a control element of the viral DNA. The second segment, which lies within the 3' end of the 69% fragment, encodes transforming sequences of the viral DNA. A retroviral control element (the long terminal repeat DNA. A retroviral control element (the long terminal repeat DNA of Harvey murine sarcoma virus) will activate the 2.3-kb segment at the 3' end of the 69% fragment to transform the mouse cells.

Animals↗
PubMed1984

Further genetic localization of the transforming sequences of the p21 v-ras gene of Harvey murine sarcoma virus.

The sequences encoding the 21-kilodalton transforming protein (p21 ras) of Harvey murine sarcoma virus have previously been localized genetically to a 1.3-kilobase segment of the viral DNA (E. H. Chang, R. W. Ellis, E. M. Scolnick, and D. R. Lowy, Science 210:1249-1251, 1980). Within this segment, DNA sequence analysis has found a single open reading frame large enough to encode the viral p21 (R. Dhar, R. W. Ellis, T. Y. Shih, S. Oroszlan, B. Shapiro, J. Maizel, D. Lowy, and E. M. Scolnick, Science 217:934-937, 1982). There are three potential in-frame ATG initiation codons at the 5' end of this open reading frame. By constructing a mutant of Harvey murine sarcoma virus DNA from which the first two ATG codons of this open reading frame have been deleted, we now show by transfection of the mutant viral DNA into NIH 3T3 cells that only the third ATG codon is necessary and sufficient for synthesis of the viral p21 and for cellular transformation.

Animals↗
PubMed1983

Characterization of a human colon/lung carcinoma oncogene.

DNA sequences capable of inducing oncogenic transformation of NIH3T3 mouse cells are found in a number of human tumour cell lines. When DNAs of these cell lines are applied to monolayer cultures of the mouse fibroblasts, foci of transformed cells are observed 2-3 weeks later. DNA from cells of such primary foci can be used in turn to induce foci in a second cycle of gene transfer. The human DNA sequences responsible for transformation have been called oncogenes, the best characterized of which is closely related to the Harvey murine sarcoma virus oncogene. Here we present a characterization of an oncogene which we found originally to be present in DNA of the SW480 colon carcinoma cell line. We indicate its structural outlines and demonstrate, in extension of reported results, its presence in an activated form in the genome of several types of human tumour cell lines as well as in biopsy tissue from an adenocarcinoma of the large bowel. We identify this tumour oncogene with c-Ki-ras2, one of two known members of the Kirsten ras family of human proto-oncogenes, extending a series of recent reports which have demonstrated homologies between human oncogenes and those of Harvey and Kirsten murine sarcoma viruses. The c-Ki-ras2 oncogene of several tumour cell lines is shown to be amplified.

Colonic Neoplasms↗
PubMed1983

The transforming function of bovine papillomavirus DNA.

When bovine papillomavirus (BPV) or its 7.9-kilobase full viral DNA genome induces focal transformation of mouse cells, the viral DNA is maintained in the transformed cells as multiple episomal copies. This transforming capacity and maintenance of the episomal state previously has been localized to a 69% subgenomic fragment of the viral DNA genome. We now have characterized further the BPV DNA sequences that can encode the transforming function. We first created a series of BPV DNA deletion mutants and correlated the location of the deletions with the capacity of the deleted viral DNAs to induce transformation of mouse cells. The results indicated that two discontinuous segments of the viral DNA were required for transformation. One segment, near the 5' end of the 69% transforming fragment, probably represents a control element of the viral DNA. The second segment, which lies within the 3' end of the 69% fragment, encodes transforming sequences of the viral DNA; ligation of a retroviral control element (the long terminal repeat DNA of Harvey murine sarcoma virus) to the 2.3-kilobase segment at the 3' end of the 69% fragment induces transformation of mouse cells. In contrast to mouse cells transformed by the full-length BPV DNA genome, the cells transformed by the deleted BPV DNA genomes contained few viral DNA copies; at least some copies appeared to be integrated. We conclude that different viral functions mediate cellular transformation and maintain the viral DNA in its episomal state.

Animals↗
PubMed1983

Nucleotide sequence of the 3' end of MCF 247 murine leukemia virus.

We isolated DNA clones of MCF 247, a leukemogenic, recombinant type C virus obtained from the thymus of an AKR mouse. We determined the nucleotide sequence of the viral long terminal repeat (LTR) and the 3' end of env, and we compared the sequences to corresponding sequences of the genome of Akv virus, the putative ecotropic parent of MCF 247. By analogy with Moloney leukemia virus, we identified the amino terminus of Prp15E, the C-terminal proteolytic cleavage product of env and precursor to mature virion p15E. In MCF 247 the presumptive Prp15E is encoded by a 603-nucleotide open reading frame. The majority of this sequence is identical to that of Akv. However, a recombination event near the 3' end of the Prp15E-coding region introduces nonecotropic sequences into MCF 247, and these extend to the 3' end through the U3 portion of the LTR. The U3 regions of Akv and MCF 247 are about 83% homologous. The R and U5 regions of the LTR of MCF 247 and Akv are identical. Large RNase T1-resistant oligonucleotides analyzed previously in numerous ecotropic and MCF viral genomes were located within the Akv and MCF 247 DNA sequences. The resulting precise T1 oligonucleotide maps of the 3' ends of MCF viral genomes reveal that the biologically defined, leukemogenic class I MCFs isolated from thymic neoplasms of inbred mice all share the sequence pattern seen in MCF 247, a representative of this group; they possess recombinant Prp15E genes and derive U3 from their nonecotropic parents.

Amino Acid Sequence↗
PubMed1982

Mechanism of activation of a human oncogene.

The oncogene of the human EJ bladder carcinoma cell lines arose via alteration of a cellular proto-oncogene. Experiments are presented that localize the genetic lesion that led to activation of the oncogene. The lesion has no affect on levels of expression of the oncogene. Instead, it affects the structure of the oncogene-encoded protein.

Base Sequence↗
PubMed1982

Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus.

A normal human gene homologous to the p21 ras oncogene of Harvey murine sarcoma virus induced oncogenic transformation and high p21 ras levels in murine fibroblasts when this gene was ligated to a control element (the long terminal repeat) from a murine or feline retrovirus. These results indicate that high levels of a gene product encoded by a normal human oncogene can induce tumorigenic transformation.

Animals↗