MYC-Induced Cyclin D2 Genomic Instability in Murine B Cell Neoplasms

Mushinski, J F; Hanley‐Hyde, Joan; Rainey, G. Jonah; Kuschak, Theodore I.; Taylor, C.; Fluri, Monika; Stevens, Leslie M.; Henderson, Darren W.; Mai, Sabine

doi:10.1007/978-3-642-60162-0_23

Cited by 4 publications

(4 citation statements)

References 19 publications

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“…In mammalian cells, overexpression of c-Myc increases the number of DNA double strand breaks (DSBs), as assayed by the level of γ-H2A.X, a phospho-histone marker of DSBs [9], [11]–[13], [15]. To determine if this is a conserved feature of Myc family proteins, we overexpressed Drosophila Myc in the dorsal compartment of the larval wing imaginal disc using apterous-Gal4 (ap-Gal4) and showed that this led to a ∼2-fold increase in the number of γ-H2A.X positive cells (Figure S1).…”

Section: Resultsmentioning

confidence: 99%

Myc-Dependent Genome Instability and Lifespan in Drosophila

et al. 2013

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The Myc family of transcription factors are key regulators of cell growth and proliferation that are dysregulated in a large number of human cancers. When overexpressed, Myc family proteins also cause genomic instability, a hallmark of both transformed and aging cells. Using an in vivo lacZ mutation reporter, we show that overexpression of Myc in Drosophila increases the frequency of large genome rearrangements associated with erroneous repair of DNA double-strand breaks (DSBs). In addition, we find that overexpression of Myc shortens adult lifespan and, conversely, that Myc haploinsufficiency reduces mutation load and extends lifespan. Our data provide the first evidence that Myc may act as a pro-aging factor, possibly through its ability to greatly increase genome instability.

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Section: Resultsmentioning

confidence: 99%

Myc-Dependent Genome Instability and Lifespan in Drosophila

et al. 2013

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“…Results in a More Rapid Progression toward Genomic Instability-In addition to cell cycle defects involving G 1 /S progression, cyclin E and c-Myc protein deregulation is involved in the generation of chromosomal instability (16,20,22,25,27,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) and correlates with tumor formation (18 -22, 25, 41, 51-64). Because c-Myc and cyclin E levels are increased in pin1 Ϫ/Ϫ cells, we evaluated the pin1 Ϫ/Ϫ cells for markers of genomic instability.…”

Section: Immortilization Of Pin1 ϫ/ϫ Mefs With a Dominant Negative P53mentioning

confidence: 99%

“…In support of this hypothesis, we have previously reported that c-Myc is stabilized in the absence of Pin1 (5). Since Myc and Ras collaborate to transform rodent cells (47), it seemed plausible that the addition of oncogenic Ras alone to Pin1 tion of these cells can be accelerated by the addition of another oncoprotein, such as Myc. Thus, MEFs expressing p53 DD and Ras were less efficiently transformed compared with MEFs expressing p53 DD , Ras, and Myc, and the MEFs only containing p53 DD and Ras formed significantly fewer colonies in soft agar than MEFs containing p53 DD , Ras, and Myc (73).…”

Section: The Absence Of Pin1 Sensitizes Cells To More Aggressive Tranmentioning

confidence: 99%

The Loss of PIN1 Deregulates Cyclin E and Sensitizes Mouse Embryo Fibroblasts to Genomic Instability

Yeh¹,

Lew

Means

2006

Journal of Biological Chemistry

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During the G 0 /G 1 -S phase transition, the timely synthesis and degradation of key regulatory proteins is required for normal cell cycle progression. Two of these proteins, c-Myc and cyclin E, are recognized by the Cdc4 E3 ligase of the Skp1/Cul1/Rbx1 (SCF) complex. SCF Cdc4 binds to a similar phosphodegron sequence in c-Myc and cyclin E proteins resulting in ubiquitylation and degradation of both proteins via the 26 S proteosome. Since the prolyl isomerase Pin1 binds the c-Myc phosphodegron and participates in regulation of c-Myc turnover, we hypothesized that Pin1 would bind to and regulate cyclin E turnover in a similar manner. Here we show that Pin1 regulates the turnover of cyclin E in mouse embryo fibroblasts. Pin1 binds to the cyclin E-Cdk2 complex in a manner that depends on Ser 384 of cyclin E, which is phosphorylated by Cdk2. The absence of Pin1 results in an increased steady-state level of cyclin E and stalling of the cells in the G 1 /S phase of the cell cycle. The cellular changes that result from the loss of Pin1 predispose Pin1 null mouse embryo fibroblasts to undergo more rapid genomic instability when immortalized by conditional inactivation of p53 and sensitizes these cells to more aggressive Ras-dependent transformation and tumorigenesis.Mitogenic stimuli initiate a sequence of events that result in the entry of quiescent cells into S phase (1). Critical for this important transition is the ordered synthesis and degradation of transcription factors such as c-Jun and c-Myc (Myc) and cyclins such as cyclin D and cyclin E (1). Deregulation of the turnover of these proteins, such that they remain active at inappropriate times during cell cycle progression, is frequently found in human cancer. Thus, an understanding of the molecular mechanisms that regulate protein turnover is crucial to provide insight into the oncogenic process. Three proteins important for the progression of cells into S phase, c-Jun, c-Myc, and cyclin E, are ubiquitylated by a common member of the Skp1/ Cul1/Rbx1 (SCF) 3 group of ubiquitin enzymes in which the F-box component, which serves as the ubiquitin E3 ligase, is Cdc4 (SEL-10, Fbw7, Ago) (2). SCF Cdc4 binds to a component of each protein that has been termed the "phosphodegron" (3) to promote the ubiquitylation and degradation of these proteins via the 26 S proteosome. c-Jun and Myc have an additional binding protein in common, the peptidyl prolyl cis/trans-isomerase Pin1, which binds and isomerizes prolyl bonds in the context of phospho-Ser/ Thr-Pro motifs (4, 5).Previously, we described the mechanism by which Pin1 promotes Myc degradation (5). The Cdc4 phosphodegron of Myc is present in a domain termed Myc box 1 (MB1), containing the sequence LPpTPPLpSP (where pT represents phosphothreonine and pS represents phosphoserine), in which the two phosphorylation events occur sequentially and are catalyzed by ERK (Ser 62 ) and GSK3␤ (Thr 58 ), respectively (6, 7). Pin1 binds to the doubly phosphorylated motif in a manner requiring phospho-Thr 58 and promotes a conformationa...

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“…The aim of this chapter is to discuss accumulating evidence that expression of c-Myc and other oncoproteins can compromise genomic integrity, how this may contribute to tumorigenesis, and to consider some of the potential mechanisms involved. In addition to other chapters in this volume, we refer the reader to the following excellent reviews detailing the diverse biological effects of the c-Myc protein on cell growth, proliferation, apoptosis, and differentiation [4][5][6][7][8][9][10].…”

Section: Overviewmentioning

confidence: 99%