Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of human diploid fibroblast cell clones were developed by DNA transfection with either wild-type SV40 T-antigen (SV40 T) or T-antigen mutants defective in its various functional domains. Cell clones expressing the wild-type SV40 T were significantly radioresistant as compared with clones transfected with the neo gene only (D0 = 192 +/- 13 vs 127 +/- 19). This radioresistance persisted in post-crisis, immortalized cell lines. A series of mutants with point or deletion mutations within each functionally active domain of SV40 T were also examined for their ability to alter radiosensitivity and induce morphological transformation. Cell clones transfected with T-antigen mutants defective in nuclear localization or origin binding showed increased radioresistance similar to clones transfected with wild-type T-antigen, and expressed morphological changes characteristic of SV40 T-transfected cells. A retinoblastoma susceptibility gene (RB) binding defective mutant showed moderately increased radioresistance (D0 = 174 +/- 10). However, cell clones transfected with three different p53 binding defective mutants showed no change in radiosensitivity (D0 = 132 +/- 5) as compared with neo gene transfected controls. Transfection with T-antigen mutants defective in either the RB or p53 binding domain yielded no morphological alterations characteristic of transformation. These data suggest that the SV40 T/p53 complex may be of importance in the radioresistance phenotype.
...
PMID:Transformation and radiosensitivity of human diploid skin fibroblasts transfected with SV40 T-antigen mutants defective in RB and P53 binding domains. 135 59

We present a murine model of trilateral retinoblastoma. Ocular retinoblastoma and central nervous system tumors are observed in a line of mice formed by the transgenic expression of SV40 T-antigen. An oncogenic protein known to bind to the retinoblastoma gene product (p105-Rb) is specifically expressed within retinal cells in this model. All animals that carry this genetic alteration develop multifocal retinal tumors. Midbrain tumors are observed in 15% of ocular tumor-bearing animals, and these arise ventral to the cerebral aqueduct at the level of the pineal gland. Both ocular and central nervous system neoplasms are heritable in heterozygous offspring through 10 sequential generations of breeding. Retinal tumors display the gross appearance, invasive properties, light and electron microscopic features, and immunohistochemical staining characteristics of human retinoblastoma. The light and electron microscopic characteristics as well as immunocytochemical features of undifferentiated midline central nervous system neoplasms further correlate with human trilateral retinoblastoma. We postulate an alternative mechanism of retinoblastoma tumorigenesis that involves functional inactivation of retinoblastoma protein locally in the face of an intact retinoblastoma gene locus.
...
PMID:A transgenic mouse model for trilateral retinoblastoma. 169 69

T antigen is able to transactivate gene expression from the simian virus 40 (SV40) late promoter and from several other viral and cellular promoters. Neither the mechanisms of transactivation by T antigen nor the regions of T antigen required for this activity have been determined. To address the latter point, we have measured the ability of a set of SV40 large T antigen mutants to stimulate gene expression in CV-1 monkey kidney cells from the SV40 late promoter and Rous sarcoma virus (RSV) long terminal repeat (LTR) promoter. Transactivation, although reduced, was retained by an N-terminal 138-amino-acid fragment of T antigen. Mutants with alterations at various locations within the N-terminal 85 amino acids transactivated the RSV LTR promoter less well than did wild-type T antigen. Most of these were also partially defective in their ability to transactivate the SV40 late promoter. Two mutants with lesions in the DNA-binding domain that were unable to bind to SV40 DNA were completely defective for transactivation of both promoter, while a third mutant with a lesion in the DNA-binding domain which retained origin-binding activity transactivated both promoters as well as did wild-type T antigen. Only a low level of transactivation was seen with mutant T antigens which had lesions in or near the zinc finger region (amino acids 300 to 350). Mutations which caused defects in ATPase activity, host range/helper function, binding to p53, binding to the retinoblastoma susceptibility protein, or nuclear localization had little or no effect on transactivation. These results suggest that N-terminal portion of T antigen possesses an activation activity. The data are consistent with the idea that the overall conformation of T antigen is important for transactivation and that mutations in other regions that reduce or eliminate transactivation do so by altering the conformation or orientation of the N-terminal region so that its ability to interact with various targets is diminished or abolished.
...
PMID:Mapping the transcriptional transactivation function of simian virus 40 large T antigen. 185 53

The binding of insulin and insulin-like growth factor I (IGF-I) and their effect on amino acid and neurotransmitter transport was studied in cultured human Y79 retinoblastoma cells. Y79 cells possess specific receptors for both insulin and IGF-I. Insulin binding to Y79 cells is characterized by a curvilinear Scatchard plot suggesting a two-site or two-affinity binding system. In contrast, IGF-I binding has a linear plot indicative of a one-site, one-affinity binding system. The uptake of glycine, a putative neurotransmitter in the retina occurs by a specific transport system in Y79 cells, independent of the uptake of other neutral amino acids. The uptake of glycine was increased 25-50% by either insulin or IGF-I. The response to insulin or IGF-I on glycine uptake is gradual and concentration dependent. The accumulation of other amino acids and putative retinal neurotransmitters by Y79 cells was not significantly affected by insulin of IGF-I. In addition, the activity of Na+/K+-ATPase was not influenced. The analysis of high affinity glycine uptake indicates that insulin and IGF-I are stimulating glycine transport by increasing the V'max without significantly affecting the K'm. Further analysis suggests that insulin and IGF-I are causing a recruitment of additional glycine transporters at the cell surface or activating otherwise nonfunctional transporters by an unexplained mechanism. Because of the implication that glycine responds as a neuroactive amino acid in Y79 cells these studies suggest that insulin and IGF-I may influence neuroactivity in the human retina by regulating the transport of glycine.
...
PMID:Amino acid and putative neurotransmitter transport in human Y79 retinoblastoma cells. Effect of insulin and insulin-like growth factor. 288 1

Serum-free cultures of normal human buccal epithelial cells were transfected with a plasmid containing the SV40 T-antigen (SV40T) gene. Two major lines developed that showed extended lifespans (between 30 and 40 weeks) as compared with the controls (approximately 6 weeks). Continued growth through one or two crises generated several sublines. They expressed the epithelial marker keratin and also exhibited nuclear expression of SV40T. The lines showed abnormal karyotypes with both numerical and structural aberrations and variably responded to agents that normally inhibit growth and/or induce terminal differentiation, i.e. transforming growth factor-beta 1 and fetal bovine serum. One of the lines, termed SVpgC2a, developed into an apparently immortal line, since it had undergone more than 700 population doublings from over 2 years in culture. Further characterization of this line demonstrated its clonal origin, with integration of two copies of SV40T at the same site and the presence of both normal retinoblastoma and wild-type p53 proteins. This line showed high resistance to growth inhibition by transforming growth factor-beta 1 and serum similar to that shown by buccal carcinoma cell line SqCC/Y1. Neither SVpgC2a nor its parental lines were tumorigenic when injected into athymic nude mice, whereas the SqCC/Y1 cells induced tumors. The various lines with extended but finite lifespans, complemented by one immortalized line, which retained non-malignant properties upon extended culture, provide a battery of model systems that will be useful for studying mechanisms of human oral carcinogenesis.
...
PMID:Characterization of human buccal epithelial cells transfected with the simian virus 40 T-antigen gene. 758 60

The protein product of the retinoblastoma tumor suppressor gene (RB) has been demonstrated to bind c-Myc protein (Myc) in vitro. To determine whether RB regulates Myc transcriptional activity in vivo, GAL4-Myc chimeric expression plasmids were generated and cotransfected with a RB expression plasmid and a GAL4-dependent reporter plasmid. RB stimulated GAL4-Myc-mediated transcription, dependent upon a domain(s) in the amino-terminus of Myc. The stimulation of Myc-mediated transcription by RB was cell-type specific and was inhibited by SV40 T-antigen, but not by a T-antigen mutant defective in RB-binding. Moreover, RB mutants containing mutations in domain B of RB pocket were significantly reduced in their ability to stimulate GAL4-Myc mediated transcription. To determine whether RB and Myc interact in vivo either directly or indirectly, a two hybrid system was used where GAL4-Rb and Myc-VP16 expression constructs were cotransfected with a GAL4-dependent reporter plasmid. A significant increase of GAL4-dependent transcription was observed, dependent upon the presence of both GAL4-Rb and Myc-VP16 fusion proteins. Mutational analysis of the Myc-VP16 chimeric proteins suggests that the amino-terminus of Myc is essential for the interaction with RB. These results demonstrate that RB can regulate Myc-mediated transcription in vivo in a cell-type specific manner through protein-protein interactions.
...
PMID:The retinoblastoma susceptibility gene product regulates Myc-mediated transcription. 783 35

Although most RNA viral genomes (and related cellular retroposons) can evolve at rates a millionfold greater than that of their host genomes, some of the small DNA viruses (polyomaviruses and papillomaviruses) appear to evolve at much slower rates. These DNA viruses generally cause host species-specific inapparent primary infections followed by life-long, benign persistent infections. Using global progressive sequence alignments for kidney-specific Polyomaviridae (mouse, hamster, primate, human), we have constructed parsimonious evolutionary trees for the viral capsid proteins (VP1, VP2/VP3) and the large tumor (T) antigen. We show that these three coding sequences can yield phylogenetic trees similar to each other and to that of their host species. Such virus-host "co-speciation" appears incongruent with some prevailing views of viral evolution, and we suggest that inapparent persistent infections may link virus and most host evolution. Similarity analysis identified three specific regions of polyoma regulatory gene products (T antigens) as highly conserved, and two of these regions correspond to binding sites for host regulatory proteins (p53, the retinoblastoma gene product p105, and the related protein p107). The p53 site overlaps with a conserved ATPase domain and the retinoblastoma site corresponds to conserved region 1 of E1A protein of adenovirus type 5. We examined the local conservation of these binding sequences and show that the conserved retinoblastoma binding domain is characteristic and inclusive of the entire polyomavirus family, but the conserved p53-like binding domain is characteristic and inclusive of three entire families of small DNA viruses: polyomaviruses, papillomaviruses, and parvoviruses. The evolution of small-DNA-virus families may thus be tightly linked to host evolution and speciation by interaction with a subset of host regulatory proteins.
...
PMID:Coevolution of persistently infecting small DNA viruses and their hosts linked to host-interactive regulatory domains. 848 26

The SNF2/Brahma proteins are a class of DNA-dependent ATPases which activate gene expression by disrupting chromatin repression. They also cooperate with nuclear hormone receptors to activate transcription. Two cDNAs encoding chicken homologues of the SNF2/Brahma proteins have been isolated from chicken haematopoietic libraries. The encoded proteins closely resemble the human homologues, hBRM and BRG1, and the chicken homologues have therefore been termed cBRH and cBRG1. Homology is conserved in five characteristic domains: an N-terminal domain that binds the SNF11 protein, a conserved domain A of unknown function, a central ATPase domain, a domain that binds the retinoblastoma tumor suppressor protein Rb, and a C-terminal bromodomain of unknown function.
...
PMID:Isolation of cDNAs encoding chicken homologues of the yeast SNF2 and Drosophila Brahma proteins. 901 49

Simian virus 40 (SV40) encodes two proteins, large T antigen and small t antigen that contribute to virus-induced tumorigenesis. Both proteins act by targeting key cellular regulatory proteins and altering their function. Known targets of the 708-amino-acid large T antigen include the three members of the retinoblastoma protein family (pRb, p107, and p130), members of the CBP family of transcriptional adapter proteins (cap-binding protein [CBP], p300, and p400), and the tumor suppressor p53. Small t antigen alters the activity of phosphatase pp2A and transactivates the cyclin A promoter. The first 82 amino acids of large T antigen and small t antigen are identical, and genetic experiments suggest that an additional target(s) important for transformation interacts with these sequences. This region contains a motif similar to the J domain, a conserved sequence found in the DnaJ family of molecular chaperones. We show here that mutations within the J domain abrogate the ability of large T antigen to transform mammalian cells. To examine whether a purified 136-amino-acid fragment from the T antigen amino terminus acts as a DnaJ-like chaperone, we investigated whether this fragment stimulates the ATPase activity of two hsc70s and discovered that ATP hydrolysis is stimulated four- to ninefold. In addition, ATPase-defective mutants of full-length T antigen, as well as wild-type small t antigen, stimulated the ATPase activity of hsc70. T antigen derivatives were also able to release an unfolded polypeptide substrate from an hsc70, an activity common to DnaJ chaperones. Because the J domain of T antigen plays essential roles in viral DNA replication, transcriptional control, virion assembly, and tumorigenesis, we conclude that this region may chaperone the rearrangement of multiprotein complexes.
...
PMID:The amino-terminal transforming region of simian virus 40 large T and small t antigens functions as a J domain. 923 32

Human papillomaviruses (HPV) have been etiologically linked to human cervical cancer. More than 90% of cervical cancer tissues express two HPV-encoded oncoproteins E6 and E7. Both E6 and E7 proteins possess transformation activity. and together they cooperate to transform primary human keratinocytes, fibroblasts. and epithelial cells. The transforming activity of E7 is associated with its ability to bind the retinoblastoma tumor suppressor protein (Rb). However, the carboxyl-terminal mutants of E7 are also defective for transformation, suggesting that other cellular targets for E7 might exist. We screened a human placenta cDNA library by yeast two-hybrid assay using HPV 16 E7 as a bait and identified the subunit 4 (S4) ATPase of the 26 S proteasome as a novel E7-binding protein. E7 binds to S4 through the carboxyl-terminal zinc binding motif, and the binding is independent of E7 sequences involved in binding to Rb. The interaction between S4 and E7 can be easily detected by in vitro protein binding assays. Moreover, we found that E7 increases the ATPase activity of S4. A recent study has shown that, in epithelial cells, E7 degrades Rb through the 26 S proteasome pathway. We hypothesize that E7 might target Rb for degradation by 26 S proteasome through its interaction with the subunit 4 of the proteasome.
...
PMID:The human papillomavirus E7 oncoprotein functionally interacts with the S4 subunit of the 26 S proteasome. 937 93


1 2 3 4 Next >>

---