Atm Is Dispensable for p53 Apoptosis and Tumor Suppression Triggered by Cell Cycle Dysfunction

Liao, Mai Jing; Yin, Chaoying; Barlow, Carrolee; Wynshaw‐Boris, Anthony; Dyke, Terry Van

doi:10.1128/mcb.19.4.3095

Cited by 41 publications

(24 citation statements)

References 43 publications

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“…The discrepancy in the ATM requirement for apoptosis in our K5 Myc model and this T antigen model may be due to differences in the oncogenic signal or to tissue-specific differences between the choriod plexus and the epidermis. Interestingly, inactivation of Atm did not accelerate tumor development in the T antigen transgenic mouse model (59). Thus, an oncogenic stress that does not require ATM to activate p53 and induce apoptosis does not cooperate with the absence of ATM to promote tumor development.…”

Section: Discussionmentioning

confidence: 98%

“…A previous study using a different transgenic mouse model demonstrated that p53 induction and apoptosis induced by another type of oncogenic stress were unaffected by the absence of ATM (59). In this transgenic model, a fragment of SV40 T antigen, which binds and inactivates Rb family members but not p53, is expressed in the brain choriod plexus epithelium.…”

Section: Discussionmentioning

confidence: 99%

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ATM promotes apoptosis and suppresses tumorigenesis in response to Myc

Pusapati

Rounbehler

Hong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

134

116

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Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of ␥H2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development.p53 ͉ DNA damage

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

ATM promotes apoptosis and suppresses tumorigenesis in response to Myc

Pusapati

Rounbehler

Hong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

134

116

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“…The creation of Atm-deficient mice (allele designation Atm ins5790neo ) has been described previously (1). Progeny of heterozygote matings were genotyped by PCR (9). Rag1-deficient mice (C57BL/6J-sv/129; Jackson Labs) were identified phenotypically by flow cytometric analysis of peripheral blood lymphocytes as described previously (14).…”

Section: Methodsmentioning

confidence: 99%

RAG-Mediated V(D)J Recombination Is Not Essential for Tumorigenesis in Atm-Deficient Mice

Petiniot

Weaver²,

Vacchio³

et al. 2002

Molecular and Cellular Biology

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Atm-deficient mice die of malignant thymic lymphomas characterized by translocations within the Tcr␣/␦ locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA (dsDNA) breaks that occur during RAG-dependent V(D)J recombination. We recently demonstrated that development of thymic lymphoma in Atm ؊/؊ mice was not prevented by loss of RAG-2. Thymic lymphomas that developed in Rag2 ؊/؊ Atm ؊/؊ mice contained multiple chromosomal abnormalities, but none of these involved the Tcr␣/␦ locus. These findings indicated that tumorigenesis in Atm ؊/؊ mice is mediated by chromosomal translocations secondary to aberrant responses to dsDNA breaks and that V(D)J recombination is an important, but not essential, event in susceptibility. In contrast to these findings, it was recently reported that Rag1 ؊/؊ Atm ؊/؊ mice do not develop thymic lymphomas, a finding that was interpreted as demonstrating a requirement for RAG-dependent recombination in the susceptibility to tumors in Atm-deficient mice. To test the possibility that RAG-1 and RAG-2 differ in their roles in tumorigenesis, we studied Rag1 ؊/؊ Atm ؊/؊ mice in parallel to our previous Rag2 ؊/؊ Atm ؊/؊ study. We found that thymic lymphomas occur at high frequency in Rag1 ؊/؊ Atm ؊/؊ mice and resemble those that occur in Rag2 ؊/؊ Atm ؊/؊ mice. These results indicate that both RAG-1 and RAG-2 are necessary for tumorigenesis involving translocation in the Tcr␣/␦ locus but that Atm deficiency leads to tumors through a broader RAG-independent predisposition to translocation, related to a generalized defect in dsDNA break repair.Ataxia telangiectasia (AT) is an autosomal recessive disease caused by mutation of the ataxia telangiectasia mutated (ATM) gene (16). Absence of the ATM protein, which plays an important role in cellular responses to the presence of doublestranded DNA (dsDNA) breaks and induction of cell cycle checkpoints (6, 18), results in a pleiotrophic phenotype characterized by progressive cerebellar ataxia, ocular telangiectasias, immunodeficiencies, increased sensitivity to ionizing radiation, and increased incidence of lymphoid cancers (2,17,20). While the exact pathophysiological mechanism relating the genetic defect to the clinical manifestations of the disease has not been elucidated, it is plausible that several components of the AT phenotype, including the predisposition to development of lymphoid malignancies, result from aberrant recognition and repair of dsDNA breaks such as those that normally occur during V(D)J recombination in lymphoid cells (15).Support for this hypothesis comes from studies of the murine model of AT. Karyotypic analysis of the thymic lymphomas that characteristically develop in Atm-deficient mice (1, 3, 22) has identified consistent translocations within the Tcr␣/␦ locus, suggesting the involvement of V(D)J recombination in the process of lymphomagenesis (11). Because V(D)J recombination is dependent upon the recombinase-activating genes (Rag1 and Rag2) (13,19), Liao and Van Dyke generated Rag1 Ϫ/Ϫ ...

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“…To generate Atm p53 double-null mice, Atm heterozygous mice were crossed to p53 knockout mice (46), and resulting double heterozygous offspring set up as breeder pairs. Genotyping was done using previously published methods for p53 and Atm (47,48). At 7 to 10 weeks of age, mice were given either 4 or 10 Gy of whole-body IR using a 60 Co source.…”

Section: Micementioning

confidence: 99%