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J Jain

Publications and source records attributed to J Jain.

33 records · Page 2Linked to original sources
PubMed1993

The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun.

Transcription of lymphokine genes in activated T cells is inhibited by the immunosuppressive agents cyclosporin A and FK506, which act by blocking the phosphatase activity of calcineurin. NFAT, a DNA-binding protein required for interleukin-2 gene transcription, is a potential target for calcineurin, cyclosporin A and FK506. NFAT contains a subunit (NFATp) which is present in unstimulated T cells and which forms a complex with Fos and Jun proteins in the nucleus of activated T cells. Here we report that NFATp is a DNA-binding phosphoprotein of relative molecular mass approximately 120,000 and is a substrate for calcineurin in vitro. Purified NFATp forms DNA-protein complexes with recombinant Jun homodimers or Jun-Fos heterodimers; the DNA-binding domains of Fos and Jun are essential for the formation of the NFATp-Fos-Jun-DNA complex. The interaction between the lymphoid-specific factor NFATp and the ubiquitous transcription factors Fos and Jun provides a novel mechanism for combinatorial regulation of interleukin-2 gene transcription, which integrates the calcium-dependent and the protein-kinase C-dependent pathways of T-cell activation.

Animals↗
PubMed1993

Analysis of the preexisting and nuclear forms of nuclear factor of activated T cells.

The nuclear factor of activated T cells (NF-AT)3 is an inducible DNA-binding protein that is essential for transcriptional induction of the IL-2 gene during T cell activation. NF-AT is thought to consist of two components: a ubiquitous, inducible nuclear component that we have identified as Fos and Jun proteins, and a preexisting, T cell-specific component (NF-ATp) which is the target for the immunosuppressive agents cyclosporin A (CsA) and FK506. We have previously shown that nuclear extracts from activated T cells form two inducible NF-AT complexes with an oligonucleotide corresponding to the distal NF-AT site of the murine IL-2 promoter, although hypotonic extracts of unstimulated T cells form a single complex containing NF-ATp. We show that the ability to detect NF-ATp in a gel shift assay, which is essential for purification and biochemical studies of this protein, is strikingly dependent on the precise sequence of the NF-AT oligonucleotide used as the labeled probe. Moreover we present evidence that the component that forms the faster-migrating ("lower") nuclear NF-AT complex is derived by a calcium-dependent, cyclosporin-sensitive, posttranslational modification of NF-ATp, and that Fos and Jun proteins stabilize its interaction with DNA. The results are discussed in the context of a model relating the two nuclear NF-AT complexes to NF-ATp.

Animals↗
PubMed1992

Nuclear factor of activated T cells contains Fos and Jun.

The nuclear factor NF-AT (ref. 1) is induced in T cells stimulated through the T-cell receptor/CD3 complex, and is required for interleukin-2 (IL-2) gene induction. Although NF-AT has not been cloned or purified, there is evidence that it is a major target for immunosuppression by cyclosporin A (CsA) and FK506 (refs 2-7). NF-AT induction may require two activation-dependent events: the CsA-sensitive translocation of a pre-existing component and the CsA-resistant synthesis of a nuclear component. Here we report that the newly synthesized nuclear component of NF-AT is the transcription factor AP-1. We show that the inducible nuclear form of NF-AT contains Fos and Jun proteins. Furthermore, we identify a pre-existing NF-AT-binding factor that is present in hypotonic extracts of unstimulated T cells. On the basis of binding, reconstitution and cotransfection experiments, we propose that activation of NF-AT occurs in at least two stages: a CsA-sensitive stage involving modification and/or translocation of the pre-existing NF-AT complex, and a CsA-insensitive stage involving the addition of newly synthesized Fos or Fos/Jun proteins to the pre-existing complex.

Animals↗
PubMed1992

The AP-1 site at -150 bp, but not the NF-kappa B site, is likely to represent the major target of protein kinase C in the interleukin 2 promoter.

Stimulation of T cells with antigen results in activation of several kinases, including protein kinase C (PKC), that may mediate the later induction of activation-related genes. We have examined the potential role of PKC in induction of the interleukin 2 (IL-2) gene in T cells stimulated through the T cell receptor/CD3 complex. We have previously shown that prolonged treatment of the untransformed T cell clone Ar-5 with phorbol esters results in downmodulation of the alpha and beta isozymes of PKC, and abrogates induction of IL-2 mRNA and protein. Here we show that phorbol ester treatment also abolishes induction of chloramphenicol acetyltransferase activity in Ar-5 cells transfected with a plasmid containing the IL-2 promoter linked to this reporter gene. The IL-2 promoter contains binding sites for nuclear factors including NFAT-1, Oct, NF-kappa B, and AP-1, which are all potentially sensitive to activation of PKC. We show that induction of a trimer of the NFAT and Oct sites is not sensitive to phorbol ester treatment, and that mutations in the NF-kappa B site have no effect on inducibility of the IL-2 promoter. In contrast, mutations in the AP-1 site located at -150 bp almost completely abrogate induction of the IL-2 promoter, and appearance of an inducible nuclear factor binding to this site is sensitive to PKC depletion. Moreover, cotransfections with c-fos and c-jun expression plasmids markedly enhance induction of the IL-2 promoter in minimally stimulated T cells. Our results indicate that the AP-1 site at -150 bp represents a major, if not the only, site of PKC responsiveness in the IL-2 promoter.

Base Sequence↗
PubMed1992

Analysis of the AP-1 sites in the IL-2 promoter.

We have investigated the role of the two AP-1 sites, located at approximately -150 and -180 bp relative to the transcription start site, in induction of the IL-2 promoter through the TCR/CD3 complex. We show that only the proximal (-150 bp) AP-1 site is functional in vitro, as judged by its ability to bind nuclear proteins from T cells stimulated with Ag or anti-CD3 epsilon. The inducible nuclear proteins binding to this site have the characteristics of AP-1, as judged by their kinetics of induction, the ability to compete and be competed efficiently by a metallothionein AP-1 site oligonucleotide, and their reaction with antibodies to Fos and Jun proteins. Mutations in the proximal AP-1 site greatly diminish or abrogate induction of the IL-2 promoter, indicating that the site is also functional in vivo. Although the distal (-180 bp) AP-1 site is incapable of direct binding to nuclear proteins from activated T cells, a mutation in this site diminishes IL-2 promoter induction, suggesting that this site may also be functional in vivo. Cotransfection of a 5' IL-2-chloramphenicol acetyltransferase plasmid with c-Fos and/or c-Jun enhances the induction of IL-2-chloramphenicol acetyltransferase activity, confirming that the IL-2 promoter contains a functional AP-1 site. Both AP-1 sites may be targets for c-Fos action, as inferred from the results of experiments in which c-Fos was cotransfected with internal deletion mutants of the IL-2 promoter lacking either AP-1 site. Northern analysis indicates that mRNAs for at least six members of the Fos/Jun family (c-fos, fosB, fra-1, c-jun, junB, and junD) are expressed in activated Ar-5 cells; thus the AP-1 sites of the IL-2 promoter may bind different dimeric Fos/Jun complexes at different times after T cell activation, perhaps mediating both positive and negative regulation of the IL-2 promoter.

Animals↗
PubMed1992

A T cell nuclear factor resembling NF-AT binds to an NF-kappa B site and to the conserved lymphokine promoter sequence "cytokine-1".

Nuclear extracts from a nontransformed murine T lymphocyte clone contained two inducible factors that bound to a nuclear factor kappa B (NF-kappa B) site. One factor was NF-kappa B, and the other was differentiated from NF-kappa B by its mobility in the electrophoretic mobility shift assay and its lack of sensitivity to protein kinase C depletion. Competition and methylation interference assays showed that the binding site for the novel factor was limited to nucleotides in the 3' half of the kappa B site. This part of the kappa B site resembled sequences in the binding site for a second inducible nuclear factor of T cells, NF-AT, as well as a conserved sequence found in several lymphokine genes, termed "cytokine-1" (CK-1). Competition and methylation interference analysis showed that both NF-AT and CK-1 sequences bound a factor similar to the novel kappa B-binding factor and that binding involved a four-nucleotide sequence (TTCC) that the kappa B, CK-1, and NF-AT sites have in common. The complexes that form with each site have characteristics of NF-AT: they are induced upon T cell receptor stimulation, are sensitive to protein synthesis inhibitors and cyclosporin A, and are not sensitive to protein kinase C depletion. Thus, a factor or factors similar to NF-AT can bind to three distinct promoter sequences which occur commonly in several T cell activation genes. These results raise the possibility that related factors binding to kappa B, CK-1, and NF-AT sequences could play a role in the coordinate induction of T cell activation genes. In addition, our results suggest that kappa B and CK-1 sites represent potential cyclosporin-sensitive promoter elements by virtue of their ability to bind an NF-AT-like factor.

Animals↗
PubMed1986

Anniversary reactions.

Explore the source record for details and available documents.

Anniversaries and Special Events↗
PubMed1984

A phase II study of cis-diamminedichloroplatinum II for advanced breast cancer. Two dose schedules.

Thirty-six (36) women with metastatic breast cancer refractory to conventional therapies were treated with cis-diamminedichloroplatinum II. Two dose schedules were used sequentially. The first 15 patients received platinum at a dose of 15 mg/m2 daily for 5 days at 28-day intervals. No response was noted in this group. Subsequently, 21 patients were treated with a dose of 100-120 mg/m2 at 28-day intervals, but with additional induced diuresis with saline, furosemide, and mannitol. Among 13 patients evaluable for response, 2 partial responses were observed.

Adult↗
PubMed1979

Blindness as initial manifestation of meningeal carcinomatosis in breast cancer.

The sudden onset of blindness in adults, with or without a history of malignancy should raise the possibility of meningeal carcinomatosis. The diagnosis is best confirmed with examination of the spinal fluid. The actual mechanism by which blindness occurs is probably a combination of tumor cuffing around the optic nerve, direct infiltration and chronic papilledema. We are reporting two patients with disseminated breast cancer who presented with blindness as the first manifestation of meningeal involvement. Treatment with whole brain radiation and intrathecal Cytosine Arabinoside produced temporary remissions, but both died a few months later of their cancer.

Blindness↗
PubMed1977

Eight-day survival without adrenal steroids.

A patient with advanced breast cancer who had undergone a total bilateral adrenalectomy in the past refused adrenal steroid replacement therapy with the idea that this would be the easiest and quickest way to end her life. However, she continued to live for more than eight days. Survival under these circumstances is unusual, and the terminal course of her illness is described.

Adrenal Cortex Hormones↗
PubMed1977

Clinical trial of nafoxidine in adrenalectomized patients with advanced breast cancer.

Antiestrogen compounds are relatively new in the treatment of breast cancer. A clinical trial of Nafoxidine therapy is being pursued in our institution. In a selected group of patients with metastatic breast cancer who had, in the past, undergone adrenalectomy, Nafoxidine therapy produced objective tumor regression in six out of ten patients. Of the six patients whose tumors contained demonstrable estrogen receptors, four showed regression (67%), one patient had stable disease, and one showed tumor progression. Of the four patients in whom estrogen receptor estimation was not done, two had, in the past, shown regression after endocrine therapy and they also showed regression of tumor with Nafoxidine therapy. In patients with metastatic breast carcinoma, who have undergone adrenalectomy in the past, a therapeutic trial with Nafoxidine may be worthwhile particularly in patients who have demonstrable estrogen receptor in the tumor of those who have in the past shown regression of tumor after endocrine therapy.

Adrenalectomy↗
PubMedDate not supplied

Neuroblastoma with concomitant giardiasis: report of a case with diagnosis by fine needle aspiration cytology.

BACKGROUND: Diagnosis of two pathologies, including a neoplasm and infectious condition, by fine needle aspiration (FNA) cytology in the same patient is rare. CASE: A 2-year-old, male child presented with fever, abdominal pain and abdominal mass. Imaging findings were strongly in favor of a neuroblastoma. FNA smears from the mass revealed fecal material containing numerous trophozoites of Giardia lamblia. FNA was repeated in view of the imaging findings. Repeat smears showed a small round cell tumor with rosettes and background filamentous/fibrillar material consistent with a neuroblastoma. Chemotherapy reduced the mass considerably. Histopathology of the resected residual mass revealed a ganglioneuroma in addition to remnants of neuroblastoma. The patient was free of disease two years after the initiation of chemotherapy. CONCLUSION: When FNA cytology shows an infectious pathology in the clinical and imaging setting of a tumor, FNA should be repeated so that an important component of the diagnosis is not missed.

Abdominal Neoplasms↗
PubMedDate not supplied

Oral leiomyosarcoma in childhood. Report of a case with fine needle aspiration cytology.

BACKGROUND: Leiomyosarcomas are rare tumors in the pediatric age group, and occurrence of this neoplasm in the oral cavity is exceedingly rare. This article highlights the fine needle aspiration (FNA) cytology diagnosis of a case of recurrent oral leiomyosarcoma in childhood. CASE: An 11-year-old male noticed a swelling in the oral cavity near the left lower jaw. It was excised and diagnosed as leiomyosarcoma on histopathology. Four months later the patient presented with a progressive swelling in the oral cavity that extended to the lower jaw. The recurrent swelling was subjected to FNA, and its cytologic features were consistent with leiomyosarcoma. There was a very good initial response to chemotherapy and radiation therapy. However, because of noncompliance with advice for further therapy, the patient had a second local recurrence and dissemination of the disease to the skeletal system, abdomen and thorax. FNA cytology diagnosis of the second locally recurrent lesion and abdominal mass were consistent with leiomyosarcoma. Immunocytochemical staining revealed a positive reaction in the cytoplasm of tumor cells for vimentin and desmin in the FNA smear and paraffin section, respectively. CONCLUSION: Fine needle aspiration cytology is a useful technique for detection of recurrence and metastasis during follow-up of childhood oral leiomyosarcoma.

Biopsy, Needle↗