Disease relevance of MCM7

• Negative regulation of DNA replication by the retinoblastoma protein is mediated by its association with MCM7 [1].
• RESULTS: MCM5 and MCM7 expression was high in 65% of ATC and negligible in normal thyroid tissue and papillary thyroid carcinomas [2].
• MCM7 amplification and overexpression are associated with prostate cancer progression [3].
• Recently, 1 of the minichromosome maintenance proteins, MCM7, was found to be a direct target of the MYCN transcription factor in neuroblastoma [4].
• Overexpressed MCM7 protein supports efficient DNA replication of Epstein-Barr virus oriP and rapid formation of tumors in nude mice without altering the activity of cellular DNA replication [5].

High impact information on MCM7

• Interaction between human MCM7 and Rad17 proteins is required for replication checkpoint signaling [6].
• Such cells show a specific defect in loading of initiator proteins Mcm4, Mcm7, and to a lesser degree, Mcm2 onto chromatin during telophase and early G1 when Mcm2-7 are normally recruited to license origins of replication [7].
• In HeLa cells, depletion of either hRad17 or hMCM7 with small-interfering RNA suppressed ultraviolet (UV) light- or aphidicolin-induced hChk1 phosphorylation, and abolished UV-induced S-phase checkpoint activation [6].
• These results demonstrate that hMCM7 plays a direct role in the transmission of DNA damage signals from active replication forks to the S-phase checkpoint machinery in human cells [6].
• Mcm2, but not RPA, is a component of the mammalian early G1-phase prereplication complex [8].

Chemical compound and disease context of MCM7

• RESULTS: The mean PIs for Ki-67 and Mcm7 were: benign luminal epithelium 0.7 and 1.2 and benign basal epithelium 0.8 and 8.2; PIN non-basal epithelium 4.9 and 10.6 and PIN basal epithelium 0.7 and 3.1; adenocarcinoma 9.8 and 22.7, respectively [9].

Biological context of MCM7

• MCM7 is not visualized by immunohistochemistry on metaphase chromosomes [10].
• The present studies were designed to investigate the signal transduction pathways controlling the expression of MCM6 and MCM7 in VSMC in response to mitogenic stimuli [11].
• An increased transcription rate accounted for MCM7 up-regulation, because the activity of the MCM7 promoter was more than 10-fold higher in ATC cells compared with normal thyroid cells [2].
• Transient transfection experiments revealed that PD98059 inhibited mitogen-induced MCM6 and MCM7 transcriptional activation [11].
• Second, ATR phosphorylates MCM2 on S108 in response to multiple forms of DNA damage and stalling of replication forks [12].

Anatomical context of MCM7

• In both the mouse and human disease, strong, full thickness staining for MCM7 was seen selectively in the epithelium of high-grade intraepithelial lesions and in frank cancer [13].
• Constitutive expression of MCM7 in a human prostate cancer cell line, DU145, resulted in markedly increased DNA synthesis and cell proliferation compared to vector-only controls, and an increased cell invasion in vitro [3].
• MCM7 immunoreactivity was found predominantly in the nuclei of cytotrophoblast and intermediate trophoblast and decreased with placental maturation [14].
• METHODS AND RESULTS: Immunohistochemical staining for MCM7 was performed on 122 samples of paraffin-embedded trophoblastic tissues including 22 normal first-trimester placentas, 12 term placentas, 12 spontaneous miscarriages (SM), 21 partial moles (PM), 44 complete hydatidiform moles (CM), and 11 choriocarcinomas (CCA) [14].
• Identification, molecular cloning, and cellular distribution of the rat homolog of minichromosome maintenance protein 7 (MCM7) in the rat testis [15].

Associations of MCM7 with chemical compounds

• The p38MAPK inhibitor SB203580, the phosphatidylinositol 3 kinase (PI3-kinase) pathway inhibitor wortmannin, and the protein kinase C pathway (PKC) inhibitor Gö 6976 did not significantly affect mitogen-induced MCM6 and MCM7 expression [11].
• OBJECTIVE: In an attempt to cast light on the mechanisms governing ATC, we evaluated MCM5 and MCM7 expression in human normal, papillary (PTC), and anaplastic thyroid samples, as well as in primary culture cells and transgenic mouse models [2].
• CONCLUSIONS: Persistent expression of Mcm2, Mcm5, and Ki-67 proteins in luminal compartments of dysplastic oesophageal squamous epithelium and dysplastic Barrett's mucosa may be diagnostic markers and imply disruption of cell cycle control and differentiation in these dysplastic epithelia [16].
• Formalin fixed paraffin embedded tissue sections from biopsy series and resections were immunostained using antibodies to Mcm2, Mcm5, and Ki-67 [16].
• Alanine substitution experiments with Mcm2 peptides showed that the phosphorylation of (5)S and (53)S by Cdc7 required the presence of an acidic amino acid adjacent to a serine residue [17].

Physical interactions of MCM7

• Third, ATR-interacting protein (ATRIP)-ATR interacts with MCM7 [12].
• Similar results were obtained after transfection of these cells with a fusion protein containing the hMCM7-binding region of hRad17 [6].
• Endogenous Plk1 co-immunoprecipitates with basal forms of Mcm7 as well as with slower migrating forms of Mcm7, induced in response to DNA damage [18].
• The cell cycle regulator p27Kip1 interacts with MCM7, a DNA replication licensing factor, to inhibit initiation of DNA replication [19].
• In the yeast two-hybrid library screening, the heart-specific FHL2 protein was found to interact with hCDC47 [20].

Enzymatic interactions of MCM7

• Mcm7 is ubiquitinated in vivo in both an E6-AP-dependent and -independent manner [21].

Regulatory relationships of MCM7

• The amino-termini of Rb and p130 strongly inhibited DNA replication in an MCM7-dependent fashion in a Xenopus in vitro DNA replication assay system [1].
• Here, we report a novel function for the cyclin-dependent kinase inhibitor p27Kip1 in inhibiting DNA replication through its interaction with MCM7, a DNA replication protein that is essential for initiation of DNA replication and maintenance of genomic integrity [19].
• We also found that expression of hCDC47 mRNA was repressed in quiescent cells but was induced at the late G1 to S phase by growth factor stimulation [22].

Other interactions of MCM7

• MCM6 and MCM7 expression was substantially increased after stimulation with platelet-derived growth factor-BB and insulin [11].
• MCM7 and its clamp-loading partner Cdc6 are highly specifically colocalized by ChIP and re-ChIP in G(1) and early S on a 198-bp segment located near the center of the initiation zone [10].
• MCM7 is recruited to multiple sites in chromatin in S and G(2), at which time it is not detected with ORC1 [10].
• We present our research on the MYCN transcription factor and target gene, MCM7, to show the utility of this approach [23].
• Interaction of chromatin-associated Plk1 and Mcm7 [18].

Analytical, diagnostic and therapeutic context of MCM7

• This structure was very similar to the mouse Mcm2/4/6/7 tetramer that was independently prepared and analysed by electron microscopy [24].
• Purified baculovirus-expressed HsCdc7-HsDbf4 selectively phosphorylates the MCM2 subunit of the minichromosome maintenance (MCM) protein complex isolated by immunoprecipitation with MCM7 antibodies in vitro [25].
• Correlation of MYCN amplification with MCM7 protein expression in neuroblastomas: a chromogenic in situ hybridization study in paraffin sections [4].
• Northern blot analyses showed that MCM7 transcripts are more abundant in the testis than other organs and confirmed the presence of the 2.4 kb MCM7 transcript at all ages studied [15].
• Western blot and immunohistochemistry experiments evidenced abundant MCM7 in proliferating gonocytes and Sertoli cells in the fetal testis [15].

References