Moderate Hypermutability of a Transgenic 
 lacZ
 Reporter Gene in 
 Myc
 -Dependent Inflammation-Induced Plasma Cell Tumors in Mice

Felix, Klaus; Polack, Axel; Pretsch, Walter; Jackson, Sharon H.; Feigenbaum, Lionel; Bornkamm, Georg-Wilhelm; Janz, Siegfried

doi:10.1158/0008-5472.can-03-2602

Cited by 5 publications

(5 citation statements)

References 68 publications

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“…One caveat to these studies is that many of these experiments were done in vitro. Several reports have suggested that MYC induces genomic instability in vivo (6,16,17). Our results are consistent with these findings.…”

Section: Discussionsupporting

confidence: 93%

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MYC Can Induce DNA Breaks In vivo and In vitro Independent of Reactive Oxygen Species

Ray¹,

Atkuri²,

Deb-Basu³

et al. 2006

Cancer Research

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MYC overexpression is thought to initiate tumorigenesis by inducing cellular proliferation and growth and to be restrained from causing tumorigenesis by inducing cell cycle arrest, cellular senescence, and/or apoptosis. Here we show that MYC can induce DNA breaks both in vitro and in vivo independent of increased production of reactive oxygen species (ROS). We provide an insight into the specific circumstances under which MYC generates ROS in vitro and propose a possible mechanism. We found that MYC induces DNA double-strand breaks (DSBs) independent of ROS production in murine lymphocytes in vivo as well as in normal human foreskin fibroblasts (NHFs) in vitro in normal (10%) serum, as measured by ;H2AX staining. However, NHFs cultured in vitro in low serum (0.05%) and/or ambient oxygen saturation resulted in ROS-associated oxidative damage and DNA single-strand breaks (SSBs), as measured by Ape-1 staining. In NHFs cultured in low versus normal serum, MYC induced increased expression of CYP2C9, a gene product well known to be associated with ROS production. Specific inhibition of CYP2C9 by small interfering RNA was shown to partially inhibit MYC-induced ROS production. Hence, MYC overexpression can induce ROS and SSBs under some conditions, but generally induces widespread DSBs in vivo and in vitro independent of ROS production. (Cancer Res 2006; 66(13): 6598-605)

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Section: Discussionsupporting

confidence: 93%

“…MYC-induced DNA damage may account for the observed proliferative arrest, senescence, and apoptosis of normal human foreskin fibroblasts (NHF) or mouse embryonic fibroblasts in vitro (9,15). Several studies have suggested that MYC may induce genomic damage in vivo (6,16,17).…”

Section: Introductionmentioning

confidence: 99%

MYC Can Induce DNA Breaks In vivo and In vitro Independent of Reactive Oxygen Species

Ray¹,

Atkuri²,

Deb-Basu³

et al. 2006

Cancer Research

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“…In addition to being involved in DDR modulation, MYC is also considered an element that causes genomic instability [ 253 , 259 , 321 – 325 ]. Several mechanisms contribute to MYC-elicited genomic instability.…”

Section: The Role Of Myc In Dna Damage Responsementioning

confidence: 99%

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

et al. 2021

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MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.

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“…The first study of this kind found no increase in the number of mutant lacI transgenes rescued from thymic tumors (43). However, two of three subsequent transgene rescue studies detected increased mutation (34,44,45). For example, a recent study reported that 5-fold more mutant lacZ transgenes were rescued from pristaneinduced mouse plasmacytomas than from normal splenocytes (45).…”

Section: Discussionmentioning

confidence: 99%

“…However, two of three subsequent transgene rescue studies detected increased mutation (34,44,45). For example, a recent study reported that 5-fold more mutant lacZ transgenes were rescued from pristaneinduced mouse plasmacytomas than from normal splenocytes (45). The results from plasmacytomas suggest a mutator phenotype, but because the mutant lacZ alleles were not sequenced, it is also possible that proliferation of mutant cells contributed to the increase observed.…”

Section: Discussionmentioning

confidence: 99%

Modeling variation in tumors in vivo

Stringer

Larson

Fischer

et al. 2005

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

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Transgenic mice that allow mutant cells to be visualized in situ were used to study variation in tumors. These mice carry the G11 placental alkaline phosphatase (PLAP) transgene, a mutant allele rendered incapable of producing its enzyme product by a frameshift caused by insertion of a tract of G:C base pairs in a coding region. Spontaneous deletion of one G:C base pair from this tract restores gene function, and cells with PLAP activity can be detected histochemically. To study tumors, the G11 PLAP transgene was introduced into the polyoma virus middle T antigen mammary tumor model. Tumors in these mice exhibited up to 300 times more PLAP ؉ cells than normal tissues. PLAP ؉ cells were located throughout each tumor. Many of the PLAP ؉ cells were singlets, but clusters also were common, with one cluster containing >30,000 cells. Comparison of these data to simulations produced by computer models suggested that multiple factors were involved in generating mutant cells in tumors. Although genetic instability appeared to have occurred in most tumors, large clusters were much more common than expected based on instability alone.microsatellites ͉ mutation ͉ instability ͉ mouse

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Moderate Hypermutability of a Transgenic lacZ Reporter Gene in Myc -Dependent Inflammation-Induced Plasma Cell Tumors in Mice

Abstract: ABSTRACT

Cited by 5 publications

References 68 publications

MYC Can Induce DNA Breaks In vivo and In vitro Independent of Reactive Oxygen Species

MYC Can Induce DNA Breaks In vivo and In vitro Independent of Reactive Oxygen Species

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

Modeling variation in tumors in vivo

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