Control of c-myc Regulation in Normal and Neoplastic Cells

Spencer, Charlotte A.; Groudine, Mark

doi:10.1016/s0065-230x(08)60476-5

Cited by 622 publications

(476 citation statements)

References 196 publications

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“…The c-myc gene can be expressed from four promoters (P0, P1, P2, P3), all of which appear to be regulated independently (Eick et al, 1990), with RNA initiated at the P2 promoter usually contributing 80-90% of total steady-state c-myc RNA in normal cells (Spencer and Groudine, 1991). RNA pol II pauses in the P2 promoter region, causing premature attenuation of P1 transcripts (Krumm et al, 1992), with the rate of RNA pol II release from the P2 pause site shown to regulate c-myc transcriptional activity (Strobl and Eick, 1992;Kohlhuber et al, 1993 resulted from P2 initiation alone, no increases in P1 transcript levels would have been observed.…”

Section: Discussionmentioning

confidence: 99%

“…(1) VHL and related genes, such as elongin A, B and C and VEGF; (2) the nuclear transcription factor c-myc, which is likely to be relevant to renal tubule development because of its expression in the developing kidney and its aberrant mRNA expression in clear cell RCC (Yao et al, 1988;Spencer and Groudine, 1991) (c-myc is of particular interest with respect to the VHL/elongin system because of the reported regulation of its gene transcript levels by transcriptional elongation (Spencer and Groudine, 1991) via differential expression of P1 and P2 promoter-initiated transcripts); (3) the c-met receptor proto-oncogene; and (4) the c-fos nuclear transcription factor as a control early-response gene.…”

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confidence: 99%

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Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes

Clifford

Czapla²,

Richards³

et al. 1998

Br J Cancer

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Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular cell (PTEC) mitogen involved in renal development. HGF/SF is the functional ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are frequently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC. pVHL binds to the positive regulatory components of the trimeric elongin (SIII) complex (elongins B and C) and has been observed to deregulate expression of the vascular endothelial growth factor (VEGF) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine potential interactions between the HGF/c-met and the VHL-mediated pathways for renal tubular growth control, we have isolated untransformed PTECs from normal kidneys, developed conditions for their culture in vitro and used these cells to investigate changes in mRNA levels of the VHL, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c-fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subunits at 8 h). This study highlights the spectrum of changes in gene expression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response. Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway. Images Figure 1

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes

Clifford

Czapla²,

Richards³

et al. 1998

Br J Cancer

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“…Activation of c-myc is found in a variety of human tumors, its deregulation often being one component of multistage carcinogenesis. 3,4 Aberrant expression of c-myc has been implicated in a wide variety of experimentally induced tumors. 5 The precise mechanism(s) by which myc activation contributes to oncogenesis is not completely defined.…”

Section: Introductionmentioning

confidence: 99%

V-myc in a simple, single gene retroviral vector causes rapid induction of leukemia and concomitant apoptosis following bone marrow transplantation

Dolnikov

Millington

et al. 1998

Leukemia

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We have previously developed an in vivo model of leukemogenesis utilizing mice reconstituted with genetically modified bone marrow cells. Based on those studies, a new single gene retroviral vector has been engineered which efficiently transfers vmyc into immature murine bone marrow cells. All reconstituted mice developed leukemia with a short latency period (5-11 weeks). In addition to hyperproliferation associated with elevated levels of PCNA, extensive apoptosis was also observed in all leukemic animals with p53 accumulating in the apoptotic cells. Whereas bax encoded protein, an effector of p53 apoptotic activity was detected in apoptotic cells, p21 Waf1 protein, a potential mediator of p53 growth suppression was not detected in these cells suggesting that v-myc-induced apoptosis was independent of the ability of p53 to induce p21 Waf1 . These results indicate that apoptosis, a part of the cellular response to v-myc expression, does not prevent leukemia development and that hyperproliferation rather than abrogation of oncogeneinduced apoptosis appears to be a critical event in v-mycinduced leukemia.

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“…[1][2][3][4] In general, c-myc gene expression has multiple activities, including potentiation and induction of programmed cell death. Amplification and overexpression of c-myc oncogene have been found in hepatoma cells.…”

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confidence: 99%

Inhibition of cell proliferation in HCC-9204 hepatoma cells by a c-myc specific ribozyme

et al. 2000

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A ribozyme (RZ) gene targeting c-myc mRNA was synthesized and cloned. Cleavage reaction showed that cleavage of the RZ was efficient and specific. The RZ gene-containing retrovirus vector pDOR-RZ was transfected into HCC-9204 hepatoma cells, which constitutively express high levels of c-myc using Lipofectamine. Positively transfected cells were selected using G418. In situ hybridization showed that both pDOR-RZ and pDOR vectors had been integrated into the chromosome of HCC-9204 cells. Dot blot hybridization indicated that expression of the RZ was only evident in pDOR-RZ-transfected HCC-9204 cells. Avidin-biotin complex enzyme-linked immunosorbent assay showed that c-myc expression was down-regulated. Chromatin aggregation into compact masses, cytoplasmic vacuole degeneration, and blurring of cytoplasm structure were observed by transmission electron microscopy in HCC-9204-RZ cells. These results suggest that the use of a c-myc mRNA cleaving enzyme could be most effective in tumor cells that are highly proliferative and constitutively express high levels of c-myc. Cancer Gene Therapy (2000) 7, 407-412

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Control of c-myc Regulation in Normal and Neoplastic Cells

Cited by 622 publications

References 196 publications

Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes

Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes

V-myc in a simple, single gene retroviral vector causes rapid induction of leukemia and concomitant apoptosis following bone marrow transplantation

Inhibition of cell proliferation in HCC-9204 hepatoma cells by a c-myc specific ribozyme

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