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MCM3  -  minichromosome maintenance complex...

Homo sapiens

Synonyms: DNA polymerase alpha holoenzyme-associated protein P1, DNA replication licensing factor MCM3, HCC5, P1-MCM3, P1.h, ...
 
 
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Disease relevance of MCM3

  • Univariate and multivariate Cox regression analysis confirmed MCM3 expression as an independent predictor of poor outcome in astrocytoma patients (P < 0.001 for both) [1].
  • RESULTS: MCM3 is overexpressed in human astrocytic tumors and elicits a cancer-restricted humoral immune response in 9.3% (9 of 97) of patients with brain tumors (n = 95) and brain metastases (n = 2) but not in healthy controls [1].
  • Interestingly, MCM3 protein was stable in MCF-7 breast cancer cells even up to 96 hours after serum starvation, whereas it was gradually degraded in normal BJ fibroblast cells [2].
  • RESULTS: We identified a minichromosome maintenance 3 (MCM3) gene that was overexpressed in various human cancers, including leukemia, lymphoma, and carcinomas of the uterine cervix, colon, lung, stomach, kidney and breast, and malignant melanoma [2].
  • Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease [3].
 

High impact information on MCM3

  • The ATP-dependent chromatin-remodeling factor SNF2h was also recruited to DS in late G1, and formed a stable complex with HDAC2 at DS. siRNA depletion of SNF2h reduced G1-specific nucleosome remodeling, histone deacetylation, and MCM3 loading at DS [4].
  • Remarkably, histone H3 acetylation of DS-bounded nucleosomes decreased during late G1, coinciding with nucleosome remodeling and MCM3 loading, and preceding the onset of DNA replication [4].
  • These binding sites are functional because they show the S-phase-dependent dissociation of Orc1 and Mcm3 known to be characteristic for prereplication complexes in mammalian cells [5].
  • To investigate the events leading to initiation of DNA replication in mammalian chromosomes, the time when hamster origin recognition complexes (ORCs) became functional was related to the time when Orc1, Orc2 and Mcm3 proteins became stably bound to hamster chromatin [6].
  • Orc1 and Mcm3 were easily eluted from chromatin during mitosis and early G(1) phase, but became stably bound during mid-G(1) phase, concomitant with the appearance of a functional pre-replication complex at a hamster replication origin [6].
 

Chemical compound and disease context of MCM3

  • In seven primary liver cancers (HCC 5, CCC 1, mixed 1), MR images (0.35 Tesla super-conducting) were compared with macroscopic appearances, and relaxation times (T1 and T2) with microscopic characteristics [7].
 

Biological context of MCM3

  • These results suggest that the up-regulation of GANP might participate in the development of Ag-driven B cells in GCs through its interaction with MCM3 [8].
  • Structure, expression, and chromosomal localization of the human gene encoding a germinal center-associated nuclear protein (GANP) that associates with MCM3 involved in the initiation of DNA replication [9].
  • The hGANP, with the domain (Map-box) capable of binding to MCM3 in B cells, might be involved in regulation of cell-cycle progression and DNA replication of GC-B cells [9].
  • Identification of Carboxyl-terminal MCM3 Phosphorylation Sites Using Polyreactive Phosphospecific Antibodies [10].
  • Furthermore, the chromatin binding of MCM3AP is temporally correlated with that of endogenous MCM3 when cells were released from mitosis [11].
 

Anatomical context of MCM3

 

Associations of MCM3 with chemical compounds

  • Expression of replication-licensing factors MCM2 and MCM3 in normal, hyperplastic, and carcinomatous endometrium: correlation with expression of Ki-67 and estrogen and progesterone receptors [12].
  • Previously shown to cause histone hyperacetylation and delocalization of replication initiation, trichostatin A treatment of cells led to a parallel qualitative change in the distribution of Mcm3, but not Orc2, across the c-myc replicator [15].
  • However, the p130 subunit of PEPC2 was phosphorylated in vitro during its incubation in the presence of [gamma-(32)P]ATP and a clarified algal extract [16].
 

Physical interactions of MCM3

 

Enzymatic interactions of MCM3

 

Regulatory relationships of MCM3

  • The addition of recombinant Map80 stimulated the amount of nuclear localized MCM3 [19].
 

Other interactions of MCM3

  • The carboxyl-terminal ATM phosphorylation sites are conserved in vertebrate MCM3 orthologs suggesting that this motif may serve important regulatory functions in response to DNA damage [10].
  • This led to the identification of phosphorylation sites in the carboxyl terminus of the minichromosome maintenance protein 3 (MCM3), a component of the hexameric MCM DNA helicase [10].
  • We showed previously that Stat1 recruits a group of nuclear proteins, among them MCM5 (minichromosome maintenance) and MCM3, for transcription activation [20].
  • Characterization of apoptosis-induced Mcm3 and Cdc6 cleavage reveals a proapoptotic effect for one Mcm3 fragment [21].
  • We compared the MCM3 protein expression levels in human cancers with conventional proliferation markers, Ki-67 and proliferating cell nuclear antigen [2].
 

Analytical, diagnostic and therapeutic context of MCM3

  • Furthermore, immunoprecipitation experiments corroborate the same where hRad51 and hRad52 proteins not only cross-talk with each other but also pull down MCM3 and MCM2/3 proteins, respectively [22].
  • Western blot and immunohistochemical analyses also revealed that MCM3 protein was elevated in most of human cancer tissues tested [2].
  • The expression of one of the identified antigens, the replication licensing factor minichromosome maintenance protein 3 (MCM3), was analyzed by immunohistochemistry in 142 primary and 27 recurrent astrocytomas (WHO grades 2-4) [1].
  • Our observations suggest the involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-mediated spontaneous apoptosis and differentiation in A253 xenografts [23].
  • SUMMARY BACKGROUND DATA: Primary resection followed by transplantation for recurrence or deterioration of liver function has been recently suggested as a rational strategy for patients with HCC 5 cm or smaller and preserved liver function [24].

References

  1. Minichromosome maintenance protein 3 elicits a cancer-restricted immune response in patients with brain malignancies and is a strong independent predictor of survival in patients with anaplastic astrocytoma. Söling, A., Sackewitz, M., Volkmar, M., Schaarschmidt, D., Jacob, R., Holzhausen, H.J., Rainov, N.G. Clin. Cancer Res. (2005) [Pubmed]
  2. Cancer-associated expression of minichromosome maintenance 3 gene in several human cancers and its involvement in tumorigenesis. Ha, S.A., Shin, S.M., Namkoong, H., Lee, H., Cho, G.W., Hur, S.Y., Kim, T.E., Kim, J.W. Clin. Cancer Res. (2004) [Pubmed]
  3. Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease. Hofmann, Y., Becker, J., Wright, F., Avner, E.D., Mrug, M., Guay-Woodford, L.M., Somlo, S., Zerres, K., Germino, G.G., Onuchic, L.F. Eur. J. Hum. Genet. (2000) [Pubmed]
  4. Cell cycle regulation of chromatin at an origin of DNA replication. Zhou, J., Chau, C.M., Deng, Z., Shiekhattar, R., Spindler, M.P., Schepers, A., Lieberman, P.M. EMBO J. (2005) [Pubmed]
  5. An episomal mammalian replicon: sequence-independent binding of the origin recognition complex. Schaarschmidt, D., Baltin, J., Stehle, I.M., Lipps, H.J., Knippers, R. EMBO J. (2004) [Pubmed]
  6. Selective instability of Orc1 protein accounts for the absence of functional origin recognition complexes during the M-G(1) transition in mammals. Natale, D.A., Li, C.J., Sun, W.H., DePamphilis, M.L. EMBO J. (2000) [Pubmed]
  7. Magnetic resonance imaging (MRI) of primary liver cancer--MRI-pathologic correlation. Ohtomo, K., Itai, Y., Furui, S., Yoshikawa, K., Yashiro, N., Iio, M. Radiation medicine. (1985) [Pubmed]
  8. A novel nuclear phosphoprotein, GANP, is up-regulated in centrocytes of the germinal center and associated with MCM3, a protein essential for DNA replication. Kuwahara, K., Yoshida, M., Kondo, E., Sakata, A., Watanabe, Y., Abe, E., Kouno, Y., Tomiyasu, S., Fujimura, S., Tokuhisa, T., Kimura, H., Ezaki, T., Sakaguchi, N. Blood (2000) [Pubmed]
  9. Structure, expression, and chromosomal localization of the human gene encoding a germinal center-associated nuclear protein (GANP) that associates with MCM3 involved in the initiation of DNA replication. Abe, E., Kuwahara, K., Yoshida, M., Suzuki, M., Terasaki, H., Matsuo, Y., Takahashi, E.I., Sakaguchi, N. Gene (2000) [Pubmed]
  10. Identification of Carboxyl-terminal MCM3 Phosphorylation Sites Using Polyreactive Phosphospecific Antibodies. Shi, Y., Dodson, G.E., Mukhopadhyay, P.S., Shanware, N.P., Trinh, A.T., Tibbetts, R.S. J. Biol. Chem. (2007) [Pubmed]
  11. The MCM3 acetylase MCM3AP inhibits initiation, but not elongation, of DNA replication via interaction with MCM3. Takei, Y., Assenberg, M., Tsujimoto, G., Laskey, R. J. Biol. Chem. (2002) [Pubmed]
  12. Expression of replication-licensing factors MCM2 and MCM3 in normal, hyperplastic, and carcinomatous endometrium: correlation with expression of Ki-67 and estrogen and progesterone receptors. Kato, K., Toki, T., Shimizu, M., Shiozawa, T., Fujii, S., Nikaido, T., Konishi, I. Int. J. Gynecol. Pathol. (2003) [Pubmed]
  13. Enhanced expression of Mcm proteins in cancer cells derived from uterine cervix. Ishimi, Y., Okayasu, I., Kato, C., Kwon, H.J., Kimura, H., Yamada, K., Song, S.Y. Eur. J. Biochem. (2003) [Pubmed]
  14. Fusion between human and Drosophila melanogaster cells induced by polyethylene glycol. Halfer, C., Del Pin, D., Dell'Oro, A. Genetica (1987) [Pubmed]
  15. Differential binding of replication proteins across the human c-myc replicator. Ghosh, M., Kemp, M., Liu, G., Ritzi, M., Schepers, A., Leffak, M. Mol. Cell. Biol. (2006) [Pubmed]
  16. In vitro phosphorylation of phosphoenolpyruvate carboxylase from the green alga Selenastrum minutum. Rivoal, J., Turpin, D.H., Plaxton, W.C. Plant Cell Physiol. (2002) [Pubmed]
  17. Functional interaction between the glucocorticoid receptor and GANP/MCM3AP. Osman, W., Laine, S., Zilliacus, J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  18. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Cortez, D., Glick, G., Elledge, S.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  19. Identification of a novel MCM3-associated protein that facilitates MCM3 nuclear localization. Takei, Y., Tsujimoto, G. J. Biol. Chem. (1998) [Pubmed]
  20. Identification of two residues in MCM5 critical for the assembly of MCM complexes and Stat1-mediated transcription activation in response to IFN-gamma. DaFonseca, C.J., Shu, F., Zhang, J.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  21. Characterization of apoptosis-induced Mcm3 and Cdc6 cleavage reveals a proapoptotic effect for one Mcm3 fragment. Schories, B., Engel, K., Dörken, B., Gossen, M., Bommert, K. Cell Death Differ. (2004) [Pubmed]
  22. Interaction of hRad51 and hRad52 with MCM complex: a cross-talk between recombination and replication proteins. Shukla, A., Navadgi, V.M., Mallikarjuna, K., Rao, B.J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  23. Involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-associated spontaneous apoptosis and differentiation in an A253 human head and neck carcinoma xenograft model. Yin, M.B., Tóth, K., Cao, S., Guo, B., Frank, C., Slocum, H.K., Rustum, Y.M. Int. J. Cancer (1999) [Pubmed]
  24. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Poon, R.T., Fan, S.T., Lo, C.M., Liu, C.L., Wong, J. Ann. Surg. (2002) [Pubmed]
 
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