Mcm7, a Subunit of the Presumptive MCM Helicase, Modulates Its Own Expression in Conjunction with Mcm1

Fitch, Michael J.; Donato, Justin J.; Tye, Bik Kwoon

doi:10.1074/jbc.m300699200

Cited by 40 publications

(39 citation statements)

References 64 publications

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“…It was demonstrated that MCMs are far more abundant than replication origins (Burkhart et al, 1995;Todorov et al, 1995), suggesting that these proteins might have functions in addition to replication licensing. Emerging evidence indicated that MCMs are also involved in transcription by either association with the carboxy-terminal domain of RNA polymerase II such as MCM2, MCM3 and MCM7 (Yankulov et al, 1999) or association with specific transcription factors such as MCM3-MCM5 complex with STAT1a (DaFonseca et al, 2001) and MCM7 with MADS-box transcription factor MCM1 (Fitch et al, 2003). Increased expression of MCM7 promotes tumor formation, progression and malignant conversion of chemical-induced skin cancer (Honeycutt et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

et al. 2010

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Minichromosome maintenance (MCM) proteins 2-7 are important in DNA replication licensing. Functional roles beyond licensing are speculated. In addition, significances in medulloblastoma (MB) remain unclear. In this study, we showed the frequent deregulation of MCM2 and MCM3 expression in 7 MB cell lines and 31 clinical samples. Moreover, DAOY and ONS76 and the clinical samples expressed elevated MCM7 transcripts with genomic gain of the gene. Immunopositivity restricted to tumor cells was found in 41, 37 and 53 out of 73 MB cases for MCM2, MCM3 and MCM7, respectively. High-MCM3 expression was associated with poor prognosis. Knockdowns of these MCMs significantly inhibited anchorage-dependent and -independent MB cell growth. The inhibition of MCM3 expression by small interfering RNA knockdown was related to G1 arrest with reduced cyclin A expression, whereas the MCM2-and MCM7-knocked-down cells arrested at G2/M with increased cyclin A expression. Interestingly, we demonstrated the links of these MCMs with cell migration and invasion using wound-healing and Transwell migration/invasion assays. Exogenous overexpression of MCM2, MCM3 and MCM7 increased anchorage-independent cell growth, and also cell migration and invasion capabilities in MB cells. The knockdown reduced the number of filopodial cells and the cells with intense stress fibers by blocking cdc42 and Rho activation. Taken together, deregulation of MCM2, MCM3 and MCM7 expression might be involved in MB tumorigenesis and we revealed undefined roles of these MCMs in control of MB cell migration and invasion.

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Section: Discussionmentioning

confidence: 99%

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

et al. 2010

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“…MCM7 has been implicated in the transcriptional regulation of its own promoter, which is induced by c-MYC. 17 However, ectopic expression of MCM7 did not influence c-MYC-mediated transcriptional activation in a transient reporter assay (data not shown). Therefore, the interaction with c-MYC is presumably not involved in the autoregulation of MCM7.…”

Section: Mcm7 Ltag and Dbc-1 Interact With Myc-box IImentioning

confidence: 99%

Large-Scale Identification of c-MYC-Associated Proteins Using a Combined TAP/MudPIT Approach

Koch¹,

Zhang²,

Verdoodt³

et al. 2007

Cell Cycle

140

117

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The c-MYC oncogene encodes a transcription factor, which is sufficient and necessary for the induction of cellular proliferation. However, the c-MYC protein is a relatively weak transactivator suggesting that it may have other functions. To identify protein interactors which may reveal new functions or represent regulators of c-MYC we systematically identified proteins associated with c-MYC in vivo using a proteomic approach. We combined tandem affinity purification (TAP) with the mass spectral multidimensional protein identification technology (MudPIT). Thereby, 221 c-MYC-associated proteins were identified. Among them were 17 previously known c-MYC-interactors. Selected new c-MYC-associated proteins (DBC-1, FBX29, KU70, MCM7, Mi2-b/CHD4, RNA Pol II, RFC2, RFC3, SV40 Large T Antigen, TCP1a, U5-116kD, ZNF281) were confirmed independently. For association with MCM7, SV40 Large T Antigen and DBC-1 the functionally important MYC-box II region was required, whereas FBX29 and Mi2-b interacted via MYC-box II and the BR-HLH-LZ motif. In addition, regulators of c-MYC activity were identified: ectopic expression of FBX29, an E3 ubiquitin ligase, decreased c-MYC protein levels and inhibited c-MYC transactivation, whereas knock-down of FBX29 elevated the concentration of c-MYC. Furthermore, sucrose gradient analysis demonstrated that c-MYC is present in numerous complexes with varying size and composition, which may accommodate the large number of new c-MYC-associated proteins identified here and mediate the diverse functions of c-MYC. Our results suggest that c-MYC, besides acting as a mitogenic transcription factor, regulates cellular proliferation by direct association with protein complexes involved in multiple synthetic processes required for cell division, as for example DNA-replication/repair and RNA-processing. Furthermore, this first comprehensive description of the c-MYC-associated sub-proteome will facilitate further studies aimed to elucidate the biology of c-MYC.

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“…We concluded from these observations that INT6 depletion affects neither nuclear export nor translation of the mcm7 mRNA. In yeast, MCM7 is able to inhibit its own transcription (Fitch et al, 2003). So we hypothesized that reduced abundance of MCM7 in S phase of INT6-silenced cells may induce higher mcm7 transcription, leading to the re-increase in MCM7 amount observed in G2.…”

Section: Int6 Depletion Activates Expression Of Mcm7mentioning

confidence: 99%

“…Unexpectedly, this fluctuation appeared to result not from an effect of INT6 silencing on MCM7 mRNA translation but from an increase in the amount of MCM7 mRNA that occurred mainly during S phase. In yeast, Mcm7 inhibits its own expression by binding to its promoter in association with Mcm1 (Fitch et al, 2003). A likely explanation to the increased transcription of mcm7 in INT6-silenced cells is that MCM7 also negatively regulates its own expression in mammalian cells.…”

Section: Regulation Of Mcm7 Amount In Response To Its Destabilizationmentioning

confidence: 99%

Human INT6 interacts with MCM7 and regulates its stability during S phase of the cell cycle

Buchsbaum

Morris²,

Bochard³

et al. 2007

Oncogene

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The mouse int6 gene is a frequent integration site of the mouse mammary tumor virus and INT6 silencing by RNA interference in HeLa cells causes an increased number of cells in the G2/M phases of the cell cycle, along with mitotic defects. In this report, we investigated the functional significance of the interaction between INT6 and MCM7, which was observed in a two-hybrid screen performed with INT6 as bait. It was found that proteasome inhibition strengthens interaction between both proteins and that INT6 stabilizes MCM7. Removal of MCM7 from chromatin as replication proceeds was accelerated in INT6-silenced cells and reduced amounts of protein were transiently observed, followed by a correction resulting from stimulation of mcm7 gene expression. Synchronized cells depleted for either INT6 or MCM7 display a reduction in thymidine incorporation and a reinforced association of RPA and claspin with chromatin. These data show that INT6 stabilizes chromatin-bound MCM7 and that alteration of this effect is associated with replication deficiency.

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Mcm7, a Subunit of the Presumptive MCM Helicase, Modulates Its Own Expression in Conjunction with Mcm1

Cited by 40 publications

References 64 publications

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

Large-Scale Identification of c-MYC-Associated Proteins Using a Combined TAP/MudPIT Approach

Human INT6 interacts with MCM7 and regulates its stability during S phase of the cell cycle

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