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ABSTRACT: The phosphatidylinositol 3-kinase (PI3K)/AKT and RAS oncogenic signalling modules are frequently mutated in sporadic human cancer. Although each of these pathways has been shown to play critical roles in driving tumour growth and proliferation, their activation in normal human cells can also promote cell senescence. Although the mechanisms mediating RAS-induced senescence have been well characterised, those controlling PI3K/AKT-induced senescence are poorly understood. Here we show that PI3K/AKT pathway activation in response to phosphatase and tensin homolog (PTEN) knockdown, mutant PI3K, catalytic, α polypeptide (PIK3CA) or activated AKT expression, promotes accumulation of p53 and p21, increases cell size and induces senescence-associated β-galactosidase activity. We demonstrate that AKT-induced senescence is p53-dependent and is characterised by mTORC1-dependent regulation of p53 translation and stabilisation of p53 protein following nucleolar localisation and inactivation of MDM2. The underlying mechanisms of RAS and AKT-induced senescence appear to be distinct, demonstrating that different mediators of senescence may be deregulated during transformation by specific oncogenes. Unlike RAS, AKT promotes rapid proliferative arrest in the absence of a hyperproliferative phase or DNA damage, indicating that inactivation of the senescence response is critical at the early stages of PI3K/AKT-driven tumourigenesis. Furthermore, our data imply that chronic activation of AKT signalling provides selective pressure for the loss of p53 function, consistent with observations that PTEN or PIK3CA mutations are significantly associated with p53 mutation in a number of human tumour types. Importantly, the demonstration that mTORC1 is an essential mediator of AKT-induced senescence raises the possibility that targeting mTORC1 in tumours with activated PI3K/AKT signalling may exert unexpected detrimental effects due to inactivation of a senescence brake on potential cancer-initiating cells.
Oncogene 09/2011; 31(15):1949-62. · 6.37 Impact Factor
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ABSTRACT: The bmi-1 gene was discovered as a frequent target of Moloney virus insertion in virally accelerated B-lymphoid tumors of E mu-myc transgenic mice and hence is thought to collaborate with the myc gene in lymphomagenesis, but its oncogenic potential has not previously been tested directly. To determine whether bmi-1 overexpression can contribute to hematopoietic neoplasia in vivo, strains of transgenic mice were generated in which bmi-1 expression was directed to the lymphoid compartment by a coupled immunoglobulin heavy chain enhancer (E mu). Although the E mu-bmi-1 transgene was expressed in both B and T cells, lymphoid development was not perturbed. Nevertheless, 14% of the mice in the strain with highest expression have developed lymphoma. Unexpectedly, most tumors were of the T-cell lineage, although one case of B lymphoma was observed. Furthermore, cross breeding E mu-bmi-1 and E mu-myc mice established that the bmi-1 transgene markedly accelerated the onset of pre-B and B lymphomas. These results demonstrate directly that bmi-1 can contribute to lymphomagenesis in the T and B cell lineages and collaborate with the myc gene in tumor development.
Oncogene 12/1993; 8(11):3161-4. · 6.37 Impact Factor
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ABSTRACT: Although the v-abl gene can provoke several types of lymphoid neoplasm, mice of a transgenic strain (E mu-v-abl 40) in which lymphocytes are targeted for expression of v-abl by a linked immunoglobulin enhancer (E mu) spontaneously develop only plasmacytomas. To determine whether other lymphocytes of this strain were susceptible to transformation, and to identify genes that can collaborate with v-abl in tumorigenesis, E mu-v-abl 40 mice were subjected to insertional mutagenesis by neonatal infection with Moloney murine leukemia virus. Tumorigenesis was accelerated moderately, but nearly all the tumors were T lymphomas. The altered tumor type may reflect both the T-cell tropism of Moloney virus and the higher level of E mu-v-abl 40 expression found in T lymphocytes than in B lymphocytes. Insertion near the c-myc, N-myc or pim-I gene was observed in 42% of the induced tumors, indicating that each of these genes may collaborate with v-abl in lymphomagenesis. Most of the accelerated tumors had a surprisingly low level of transgene expression. Thus, high expression of v-abl may not be required for Moloney-induced T lymphomagenesis.
International Journal of Cancer 11/1993; 55(4):623-9. · 5.44 Impact Factor
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ABSTRACT: The ability of Moloney murine leukemia virus to accelerate lymphomagenesis in E-myc transgenic mice is frequently associated with proviral integration within a locus denotedbmi-1. This locus contains not only thebmi-1 gene implicated as a collaborator withmyc in lymphomagenesis but also just upstream an unknown gene denotedbup. The nucleotide sequence reported here forbup cDNA and flanking genomic sequences reveals that this widely expressed gene comprises at least 7 exons and potentially encodes a polypeptide of 195 amino acid residues. Computer searches with this polypeptide sequence revealed no close homolog in the databases, nor any conserved motifs, and it is unrelated to the product of themel-13 gene, which lies just upstream from thebmi-1 homologmel-18.
Molecular Biology Reports 12/1992; 17(1):17-20. · 2.93 Impact Factor
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ABSTRACT: The ability of Moloney murine leukemia virus to accelerate lymphomagenesis in E mu-myc transgenic mice is frequently associated with proviral integration within a locus denoted bmi-1. This locus contains not only the bmi-1 gene implicated as a collaborator with myc in lymphomagenesis but also just upstream an unknown gene denoted bup. The nucleotide sequence reported here for bup cDNA and flanking genomic sequences reveals that this widely expressed gene comprises at least 7 exons and potentially encodes a polypeptide of 195 amino acid residues. Computer searches with this polypeptide sequence revealed no close homolog in the databases, nor any conserved motifs, and it is unrelated to the product of the mel-13 gene, which lies just upstream from the bmi-1 homolog mel-18.
Molecular Biology Reports 12/1992; 17(1):17-20. · 2.93 Impact Factor
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ABSTRACT: Transgenic mice bearing a mutant, activated N-ras oncogene directed to express within hematopoietic cells by an immunoglobulin enhancer (E mu) sporadically develop T-cell lymphomas and non-lymphoid tumors that may be of macrophage origin. To identify genes that can collaborate with N-ras in hematopoietic neoplasia, Moloney murine leukemia virus was used as an insertional mutagen. Infection of newborn E mu-N-ras mice with the virus greatly accelerated tumorigenesis, and nearly all the tumors proved to be T-cell lymphomas. Their variable surface phenotype (CD4+CD8-, CD4+CD8+ and CD4-CD8-) suggested that cells at several stages of T-cell development were susceptible to tumorigenesis. Southern blot analysis revealed that 68% of the tumors bore a proviral insert 5' to the c-myc gene, while 13% had an insert within the 3' untranslated region of the N-myc gene. Insertion was associated with elevated expression of these genes. Hence, activation of a myc gene appears to be the dominant pathway to tumorigenesis by insertional mutagenesis in lymphoid cells expressing a mutant ras gene. However, since many of the tumors were not transplantable, even the partnership of myc and ras may not suffice for full lymphoid malignancy.
Oncogene 06/1992; 7(5):981-6. · 6.37 Impact Factor
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ABSTRACT: To search for genes that can collaborate with myc in lymphomagenesis, we exploited retroviral insertional mutagenesis in E mu-myc transgenic mice. Moloney murine leukemia virus accelerated development of B lymphoid tumors. Three quarters contained a provirus within the known pim-1 or pim-2 loci, new loci bmi-1 and emi-1, or combinations of these. bmi-1 insertions predominated, occurring in half the tumors, and resulted in elevated bmi-1 mRNA levels. Significantly, the bmi-1 gene, which is expressed in diverse normal cells, encodes a Cys/His metal-binding motif (C3HC4) that resembles those in several DNA-binding proteins and defines a new category of zinc finger gene. Thus, myc-induced lymphomagenesis can entail the concerted action of several genes, including the presumptive nuclear regulator bmi-1.
Cell 06/1991; 65(5):753-63. · 32.40 Impact Factor
