Expression of ras oncogenes in cultured human cells alters the transcriptional and posttranscriptional regulation of cytokine genes.

Demetri, George D.; Ernst, T J; Pratt, Edward; Zenzie, Beatrice W.; Rheinwald, James G.; Griffin, James D.

doi:10.1172/jci114833

Cited by 64 publications

(26 citation statements)

References 60 publications

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“…Malignant cells are known to produce a variety of cytokines, such as hematopoietic colony-stimulating factors, interleukin 1, and interleukin 6, and it has been reported that transfection of an activated ras oncogene into normal human fibroblasts induces these cytokine genes mainly through a post-transcriptional mechanism (24). The PTHRP gene has certain characteristics of an early response gene, including the presence in PTHRP mRNAs of the AUUUA instability motifs at the 3Ј-untranslated regions (25).…”

Section: Resultsmentioning

confidence: 99%

Neoplastic Transformation of Normal Rat Embryo Fibroblasts by a Mutated p53 and an Activated ras Oncogene Induces Parathyroid Hormone-related Peptide Gene Expression and Causes Hypercalcemia in Nude Mice

Motokura

Endo²,

Kumaki³

et al. 1995

Journal of Biological Chemistry

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Parathyroid hormone-related peptide (PTHRP) is a 141-amino acid protein identified in various carcinomas associated with humoral hypercalcemia of malignancy (HHM). Although the causal role of PTHRP in HHM syndrome has been established, the molecular and cellular mechanism by which PTHRP gene is overexpressed in certain malignancies remains unknown. We have demonstrated in the present study that PTHRP secretion was markedly induced concomitantly with the formation of transformed foci after normal rat embryo fibroblasts (REFs) were co-transfected with an activated ras (ras) and a mutated form of p53 (p53-mt) genes. In either ras-or p53-mt-transfected (nontransformed) cells, only modest or barely detectable secretion of PTHRP was observed, respectively. Northern blot analysis revealed that PTHRP mRNA was markedly induced in fully transformed cells 11 days after transfection with both ras and p53-mt genes. Inhibition of RNA synthesis with actinomycin D resulted in almost complete disappearance of PTHRP mRNA at 2-3 h, suggesting a transcriptional mechanism. Transient transfection experiments revealed that PTHRP promoter activity was induced in ras ؉ p53-mt transfectants. REFs transformed by ras and p53-mt genes and thereby induced to secrete PTHRP in vitro produced aggressively growing tumors associated with HHM syndrome when injected into nude mice. These results suggest that activation of PTHRP gene is closely related to malignant transformation of normal mammalian cells and that ras and p53 may be important regulators of PTHRP gene transcription. The transfection-focus formation system of REFs should provide an excellent model to study the molecular and cellular mechanism underlying concomitant overexpression of PTHRP gene with carcinogenesis. Parathyroid hormone-related peptide (PTHRP)1 is a 141-amino acid protein identified in various carcinomas as a causative factor for humoral hypercalcemia of malignancy (HHM) (1-3). PTHRP shows structural and functional similarities to parathyroid hormone, including a sequence homology at the amino-terminal parathyroid hormone-like domain (1-3). Thus PTHRP overproduced and secreted by certain carcinomas enters the circulation (4), interacts with a common receptor for parathyroid hormone/PTHRP in bone and kidney (5), and causes hypercalcemia in cancer patients. The findings that circulating PTHRP levels are elevated in most patients with HHM (4) and that hypercalcemia is corrected by a neutralizing antibody against PTHRP in animal models of HHM (6) have further strengthened the causal role for PTHRP in the pathogenesis of HHM syndrome. Accumulating evidence suggests that PTHRP gene is expressed at low levels in a number of normal tissues and plays diverse physiological roles mainly in an autocrine/paracrine fashion (7). However, the exact molecular and cellular mechanism by which PTHRP gene is overexpressed in certain carcinomas remains unknown.Carcinogenesis is a complex, multistep process, and it has been established that oncogenes and tumor suppressor genes play the fundame...

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Section: Resultsmentioning

confidence: 99%

Neoplastic Transformation of Normal Rat Embryo Fibroblasts by a Mutated p53 and an Activated ras Oncogene Induces Parathyroid Hormone-related Peptide Gene Expression and Causes Hypercalcemia in Nude Mice

Motokura

Endo²,

Kumaki³

et al. 1995

Journal of Biological Chemistry

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“…stimulating factor (CSF), granulocyte-macophage-CSF, and interleukin-1␤ (46). Interestingly, elevated cytokine production has been demonstrated in a number of nonsmall cell lung cancer lines (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Induction of Cytosolic Phospholipase A2 by Oncogenic Ras Is Mediated through the JNK and ERK Pathways in Rat Epithelial Cells

Putten

Refaat

Dessev

et al. 2001

Journal of Biological Chemistry

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“…14,15 It is likely that this frequency of Ras deregulation in leukaemia is greatly underestimated as deregulation of GEFs 12 or GAPs, 13 overexpression of growth factor receptors, 16 or autonomous cytokine production, 17 may all lead to constitutive signalling of Ras, without mutations in Ras itself. Efforts to elucidate the precise role of Ras in leukaemia have yielded conflicting reports, as to whether deregulated signalling is an initiating factor of leukaemogenesis, 18 or whether mutations accumulate only as the disease progresses.…”

Section: Introductionmentioning

confidence: 99%

Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals

et al. 2000

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Drug resistance remains a serious limiting factor in the treatment of acute myeloid leukaemia (AML) either at initial presentation or following primary or subsequent relapses. Using specific kinase inhibitors, this study has investigated the contribution of the Ras/PI3-kinase regulated survival pathways to drug resistance and suppression of apoptosis in a cell line derived from AML (HL60). Inhibition of the Raf/MAP-kinase (ERK) pathway with a specific MAP-kinase inhibitor, apigenin did not sensitise HL60 cells to drug-induced apoptosis, indicating a lack of involvement in chemoresistance. In contrast, the PI3-kinase inhibitors, LY294002 and wortmannin, did induce a significant increase in apoptosis in combination with cytotoxic drugs. The contribution of downstream mediators of PI3-kinase, p70S6-kinase and PKB/Akt were then investigated. While inhibition of p70S6-kinase with rapamycin did not increase drug-induced apoptosis, PI3-kinase inhibition resulted in notable dephosphorylation of PKB, suggesting that the PI3-kinase/PKB survival pathway may play a major role in chemoresistance in AML. This pathway has been reported to mediate heterodimer interactions with the proapoptotic regulator, Bad. In contrast to previous studies, we found no evidence of Bad binding to anti-apoptotic Bcl-2, Bcl-X L or Mcl-1, or of alterations in Bax heterodimers. This suggests that alternative targets of PI3-kinase/PKB, distinct from the Bcl-2 family may be responsible for contributing to survival factor-mediated drug resistance in AML. Leukemia (2000) 14, 602-611.

show abstract

Expression of ras oncogenes in cultured human cells alters the transcriptional and posttranscriptional regulation of cytokine genes.

Cited by 64 publications

References 60 publications

Neoplastic Transformation of Normal Rat Embryo Fibroblasts by a Mutated p53 and an Activated ras Oncogene Induces Parathyroid Hormone-related Peptide Gene Expression and Causes Hypercalcemia in Nude Mice

Neoplastic Transformation of Normal Rat Embryo Fibroblasts by a Mutated p53 and an Activated ras Oncogene Induces Parathyroid Hormone-related Peptide Gene Expression and Causes Hypercalcemia in Nude Mice

Induction of Cytosolic Phospholipase A2 by Oncogenic Ras Is Mediated through the JNK and ERK Pathways in Rat Epithelial Cells

Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals

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