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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regional lymph node (RL) cells of patients with primary lung cancer exhibited no cytotoxicity to autologous tumor cells in a 4-hr 51Cr-release assay, but when cultured in the presence of Interleukin 2 (IL2), the RL cells did become cytotoxic to those target cells. When RL cells were included in a cytotoxic test of IL2-activated RL cells (autologous killer T cells; AKT cells) and autologous target cells, the cytotoxicity of the AKT cells was significantly inhibited in 27 out of a total of 42 cases, but this suppression was observed against neither allogeneic effector cells (seven out of nine cases) nor natural killer cells (all seven cases tested). The cytotoxicity of AKT cells to allogeneic target cells was inhibited by RL cells in three out of six cases. Nylon-wool column separation indicated that the cell population adhering to the nylon wool mediated the suppressive effect of the RL cells. These data suggested the presence of nylon-wool-adherent suppressor cells in the regional lymph nodes of patients with primary lung cancer which suppress the cytotoxicity of autologous killer lymphocytes to autologous tumor cells.
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PMID:Inhibition of cytotoxicity to autologous tumor cells by the regional lymph node cells of patients with primary lung cancer. 295 35

Tumor antigen peptides on BALB/c leukemia RL male 1 that were recognized by cytotoxic T lymphocytes were shown to be derived from a normally untranslated region of the akt proto-oncogene (Uenaka, A. et al., J. Exp. Med., 180: 1599, 1994). We show here that the murine leukemia virus (MuLV) long terminal repeat (LTR) was inserted directly into the exon of c-akt in RL male 1 leukemia and that transcription started from the cap site of the LTR. Translation appeared to start from the ATG codon created in the six nucleotides of unknown origin, which were inserted into the LTR/akt junction. The deduced molecular size is approximately M(r) 59,000 due to the addition of 33 amino acid residues to the normally expressed c-AKT protein. Western blot analysis demonstrated the presence of M(r) 59,000 molecules in an RL male 1 lysate, and their expression at about ten times the level of normal AKT molecules of M(r) 56,000, which is consistent with the increased expression of akt mRNA demonstrated by Northern blot analysis. The findings show that the molecular alteration of AKT protein by insertion of MuLV LTR is the mechanism for creating rejection antigen peptides derived from the untranslated region of akt.
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PMID:Rejection antigen peptides on BALB/c RL male 1 leukemia recognized by cytotoxic T lymphocytes: derivation from the normally untranslated 5' region of the c-akt proto-oncogene activated by long terminal repeat. 758 4

This chapter will explore the role of survival factors in suppression of apoptosis, and illustrate how survival signals play a critical role in the survival of both normal and tumor cells. Survival factors necessary for the development and maintenance of the nervous system and hemopoietic system will be surveyed. This will be followed by a detailed discussion of the role of insulin-like growth factor I (IGF-I) and its receptor in suppression of apoptosis. The importance of survival signals from the IGF-IR for development and tumorigenesis will be discussed, and results of a mutational analysis of the receptor to assign domains necessary for suppression of apoptosis will be summarized. Finally, a discussion of the signal transduction pathways involved in survival factor-signaling will review the roles played by PI-3 kinase and AKT and speculate on how activation of these kinases by survival factors might regulate the apoptotic pathway.
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PMID:Survival factors and apoptosis. 975 44

An insulin-like signaling pathway, from the DAF-2 receptor, the AGE-1 phosphoinositide 3-kinase, and the AKT-1/AKT-2 serine/threonine kinases to the DAF-16 Fork head transcription factor, regulates the metabolism, development, and life span of Caenorhabditis elegans. Inhibition of daf-18 gene activity bypasses the normal requirement for AGE-1 and partially bypasses the need for DAF-2 signaling. The suppression of age-1 mutations by a daf-18 mutation depends on AKT-1/AKT-2 signaling, showing that DAF-18 acts between AGE-1 and the AKT input to DAF-16 transcriptional regulation. daf-18 encodes a homolog of the human tumor suppressor PTEN (MMAC1/TEP1), which has 3-phosphatase activity toward phosphatidylinositol 3,4,5-trisphosphate (PIP3). DAF-18 PTEN may normally limit AKT-1 and AKT-2 activation by decreasing PIP3 levels. The action of daf-18 in this metabolic control pathway suggests that mammalian PTEN may modulate insulin signaling and may be variant in diabetic pedigrees.
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PMID:The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. 988 76

A novel tumor suppressor gene, PTEN, has recently been identified at chromosome 10q23, which is inactivated in a number of different tumor types including breast cancer. An investigation of the functional role suggested that PTEN transcriptionally represses both exogenous and endogenous c-myc expressions in human breast carcinoma cells. PTEN, when ectopically expressed in human breast carcinoma cells, exhibited an inhibition of phosphorylation of both activating residues of protein kinase B (PKB)/AKT at Ser-473 and Thr-308 without any significant alteration of AKT expression. Furthermore, introduction of PTEN into human breast carcinoma cells induced apoptotic cell death and inhibited cell growth and tumor formation in nude mice. Taken together, our data suggest that PTEN acts as a transcriptional repressor, inhibits the AKT-mediated cell survival signaling pathway, and negatively regulates human breast carcinoma cell growth. These results further emphasize the potential of PTEN as a gene therapeutic agent.
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PMID:PTEN transcriptionally modulates c-myc gene expression in human breast carcinoma cells and is involved in cell growth regulation. 1041 36

AKT1 (c-AKT, PKBalpha) is the cellular homolog of the protein-serine/threonine kinase oncogene, v-akt. AKT1 is activated through the insulin and platelet-derived growth factor signaling pathways in transfected fibroblasts, but little is known about the regulation of endogenous AKT1 in tumor cells. AKT1 levels were higher in a panel of human breast carcinoma cell lines than in breast epithelial cells, particularly those with higher HER2 expression. AKT1 activity was increased by either estradiol or IGF-I in estrogen-dependent MCF-7 cells, and both factors acted synergistically to increase AKT1 activity and promote cell proliferation. Stimulation of AKT1 activity by estradiol and IGF-I was blocked by the antiestrogen ICI 182780 and by the phosphatidylinositol-3-kinase inhibitor wortmannin. MCF-7 cells transfected with AKT1 exhibited partial estrogen- and IGF-I-independent growth and were more responsive to the combination of IGF-I and estradiol. AKT1-overexpressing MCF-7 cells were less sensitive to apoptosis induced by wortmannin. These findings suggest that AKT1 is a downstream effector of estrogen- and IGF-I-dependent proliferation and survival in hormone-responsive MCF-7 breast carcinoma cells.
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PMID:Role of AKT1 in 17beta-estradiol- and insulin-like growth factor I (IGF-I)-dependent proliferation and prevention of apoptosis in MCF-7 breast carcinoma cells. 1042 60

The tumor suppressor gene PTEN (MMAC1, TEP1) encodes a dual-specificity phosphatase and is considered a progression-associated target of genetic alterations in human gliomas. Recently, it has been reported that the introduction of wild type PTEN into glioma cells containing endogenous mutant PTEN alleles (U87MG, LN-308), but not in those which retain wild-type PTEN (LN-18, LN-229), causes growth suppression and inhibits cellular migration, spreading and focal adhesion. Here, we show that PTEN gene transfer has no effect on the chemosensitivity of the four cell lines. Further, a correlational analysis of the endogenous PTEN status of 12 human glioma cell lines with their sensitivity to seven different cancer chemotherapy drugs reveals no link between PTEN and chemosensitivity. In contrast, ectopic expression of wild type PTEN, but not the PTEN(G129R) mutant, in PTEN-mutant gliomas markedly sensitizes these cells to irradiation and to CD95-ligand (CD95L)-induced apoptosis. PTEN-mediated facilitation of CD95L-induced apoptosis is associated with enhanced CD95L-evoked caspase 3 activity. Protein kinase B (PKB/Akt), previously shown to inhibit CD95L-induced apoptosis in nonglial COS7 cells, is inactivated by dephosphorylation. Interestingly, both PTEN-mutant U87MG and PTEN-wild-type LN-229 cells contain phosphorylated PKB constitutively. Wild-type PTEN gene transfer promotes dephosphorylation of PKB specifically in U87MG cells but not in LN-229 cells. Sensitization of U87MG cells to CD95L-apoptosis by wild-type PTEN is blocked by insulin-like growth factor-1 (IGF-1). The protection by IGF-1 is inhibited by the phosphoinositide 3-OH (PI 3) kinase inhibitor, wortmannin. Although PKB is a down-stream target of PI 3 kinase, the protection by IGF-1 was not associated with the reconstitution of PKB phosphorylation. Thus, PTEN may sensitize human malignant glioma cells to CD95L-induced apoptosis in a PI 3 kinase-dependent manner that may not require PKB phosphorylation.
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PMID:PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. 1043 16

The breast cancer susceptibility gene BRCA1 encodes a nuclear phosphoprotein that acts as a tumor suppressor. Phosphorylation of BRCA1 has been implicated in altering its function, however, the pathway(s) that leads to the phosphorylation of BRCA1 has not been described. Here, a signaling pathway by which heregulin induces cell cycle-independent phosphorylation of BRCA1 was delineated. We showed that heregulin stimulation induced the phosphorylation of BRCA1 and concomitant activation of the serine/threonine kinase AKT in T47D human breast cancer cells. Heregulin-induced phosphorylation of BRCA1 was abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitors and by a dominant-negative AKT. In the absence of heregulin, the ectopic expression of the constitutively active p110 subunit of PI3K was sufficient to induce BRCA1 phosphorylation. Furthermore, the purified glutathione S-transferase/AKT kinase phosphorylated BRCA1 in vitro. We have also shown that the phosphorylation of BRCA1 by AKT occurs on the residue Thr-509, which is located in the nuclear localization signal. These results reveal a novel signaling pathway that links extracellular signals to the phosphorylation of BRCA1 in breast cancer cells.
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PMID:Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells. 1054 66

The importance of apoptosis as a natural means to eliminate unwanted or damaged cells has been realized over the past decade. Many components required to exercise programmed cell death have been identified and shown to pre-exist in most, if not all, cells. Such ubiquity requires that apoptosis be tightly controlled and suggests the propensity of cells to trigger the cellular death machinery can be regulated. Recently, several signaling pathways have been demonstrated to impact the apoptotic potential of cells, most notably the phosphatidylinositol 3' kinase (PI3'K) pathway. The 3' phosphorylated lipid products generated by this enzyme promote activation of a protein-serine kinase, PKB/AKT, which is necessary and sufficient to confer cell PI3'K-dependent survival signals. The relevance of this pathway to human cancer was revealed by the recent finding that the product of the PTEN tumor suppressor gene acts to antagonize PI3'K. This review focuses on the regulation and mechanisms by which PKB activation protects cells and the oncologic consequences of dysregulation of the pathway.
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PMID:Modulation of cellular apoptotic potential: contributions to oncogenesis. 1055

Although the interaction of matrix proteins with integrins is known to initiate signaling pathways that are essential for cell survival, a role for tumor suppressors in the regulation of these pathways has not been established. We demonstrate here that p53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase AKT/PKB. Specifically, we show that the alpha6beta4 integrin promotes the survival of p53-deficient carcinoma cells by activating AKT/PKB. In contrast, this integrin does not activate AKT/PKB in carcinoma cells that express wild-type p53 and it actually stimulates their apoptosis, in agreement with our previous findings (Bachelder, R.E., A. Marchetti, R. Falcioni, S. Soddu, and A.M. Mercurio. 1999. J. Biol. Chem. 274:20733-20737). Interestingly, we observed reduced levels of AKT/PKB protein after antibody clustering of alpha6beta4 in carcinoma cells that express wild-type p53. In contrast, alpha6beta4 clustering did not reduce the level of AKT/PKB in carcinoma cells that lack functional p53. The involvement of caspase 3 in AKT/PKB regulation was indicated by the ability of Z-DEVD-FMK, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in AKT/PKB levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of AKT/PKB in vitro. In addition, the ability of alpha6beta4 to activate AKT/PKB could be restored in p53 wild-type carcinoma cells by inhibiting caspase 3 activity. These studies demonstrate that the p53 tumor suppressor can inhibit integrin-associated survival signaling pathways.
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PMID:p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB. 1057 25


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