The role of MCM proteins in the cell cycle control of genome duplication

Kearsey, Stephen; Maiorano, Domenico; Holmes, Eddie; Todorov, Ivan

doi:10.1002/bies.950180305

Cited by 138 publications

(126 citation statements)

References 70 publications

(24 reference statements)

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“…3), the conclusion also reached by Tsugura and colleagues who recently submitted their sequence to the databases [19]. The name MCM6 has been suggested for these sequences [3,4]. Thus, the human gene described in this paper is designated MCM6 (HUGO/GDB approved gene symbol).…”

Section: Sequence Comparison With Members Of the Mcm2-7 Fa-mentioning

confidence: 60%

“…This paper is concerned with the identification of a novel gene in close proximity to LCT, which has a high level of identity to a rat intestinal crypt-cell replication factor [2]. Both the human and rat genes appear to be mammalian homologues of a yeast cell division cycle gene identified as mis5 (in Schizosaccharomyces pombe), more recently named MCM6 [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…The genes were separated into groups or families depending on where the arrest occurs. MCM6 falls into the group (MCM2-7 [3,4]) in which the arrest occurs before S-phase. The protein products appear to play a role in 'licensing' the replication of DNA [5,6] and are thought to bind to DNA after mitosis (G1) and to be removed from the DNA during replication (S phase).…”

Section: Introductionmentioning

confidence: 99%

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Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5′ end of the lactase gene on chromosome 2q21

Harvey¹,

Wang²,

Darmoul

et al. 1996

FEBS Letters

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Section: Sequence Comparison With Members Of the Mcm2-7 Fa-mentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5′ end of the lactase gene on chromosome 2q21

Harvey¹,

Wang²,

Darmoul

et al. 1996

FEBS Letters

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“…[1][2][3]. Genetic evidence suggests that these proteins are required for the initiation of DNA replication in yeast (4,5).…”

mentioning

confidence: 99%

A DNA Helicase Activity Is Associated with an MCM4, -6, and -7 Protein Complex

Ishimi

1997

Journal of Biological Chemistry

506

508

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All six minichromosome maintenance (MCM) proteins have DNA-dependent ATPase motifs in the central domain which is conserved from yeast to mammals. Our group purified MCM protein complexes consisting of MCM2, -4 (Cdc21), -6 (Mis5), and -7 (CDC47) proteins from HeLa cells by using histone-Sepharose column chromatography (Ishimi, Y., Ichinose, S., Omori, A., Sato K., and Kimura, H. (1996) J. Biol. Chem. 271, 24115-24122). The present study revealed that both ATPase activity and DNA helicase activity that displaces oligonucleotides annealed to single-stranded circular DNA are associated with an MCM protein complex. Both ATPase and DNA helicase activities were co-purified with a 600-kDa protein complex that is consisted of equal amounts of MCM4, -6, and -7 proteins. An immunodepletion of the MCM protein complex from the purified fraction using anti-MCM4 antibody resulted in the severe reduction of the DNA helicase activity. Displacement of DNA fragments by the DNA helicase suggested that it migrated along single-stranded DNA in the 3 to 5 direction, and the DNA helicase activity was detected only in the presence of hydrolyzable ATP or dATP. These results suggest that this helicase may be involved in the initiation of DNA replication as a DNA unwinding enzyme.There are at least six MCM 1 proteins that play an essential role in eukaryotic DNA replication as follows: MCM2, -3, -4 (Cdc21), -5, -6 (Mis5), and -7 (CDC47) proteins (see reviews in Refs. 1-3). Genetic evidence suggests that these proteins are required for the initiation of DNA replication in yeast (4, 5). The inactivation of human MCM2 protein with antibody consistently inhibits the initiation of DNA replication (6). Interaction between the MCM proteins has been reported in yeast (4, 7), and the protein complexes containing MCM proteins are detected in Drosophila (8), Xenopus (9), mouse (10, 11), and human cells (12)(13)(14). In human cells, MCM4, -6, and -7 proteins form a stable complex, and MCM2 is loosely associated with this complex (12,15,16). MCM3 and -5 proteins also form a stable complex (10, 13). All six of the MCM proteins contain DNA-dependent ATPase motifs in a central domain that is conserved from yeast to mammals, and these motifs are found in several enzymes that unwind the DNA duplex (17). These findings suggest that MCM protein complexes may be involved in the initiation of DNA replication as an enzyme that unwinds DNA in the origin region. However, DNA helicase activity of MCM proteins has not been reported.MCM proteins bind with chromatin before the initiation of DNA replication and are then released from the chromatin as DNA replication proceeds (18 -20). Our group found that MCM protein complexes containing MCM2, -4, -6, and -7 proteins bound tightly with histone H3 in vitro and were purified to near homogeneity by histone-Sepharose column chromatography (21). In the present study, it is shown that both ATPase and DNA helicase activities are associated with an MCM4, -6, and -7 protein complex. EXPERIMENTAL PROCEDURESPurification of MCM ...

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“…We next investigated whether CM6 antibody blocks the growth of 804G cells at a particular stage in the cell cycle. For these studies we made use of an antibody against BM28/hMCM2, which is a member of the recently defined family of MCM proteins thought to play an essential role in the regulation of DNA replication (Kearsey et al, 1996). The BM28 protein as well as other members of the MCM family are found tightly bound to chromatin during the G1 phase of the cell cycle and are gradually released during S phase (Todorov et al, 1995;Krude et al, 1996).…”

mentioning

confidence: 99%

A Cell Signal Pathway Involving Laminin-5, α3β1 Integrin, and Mitogen-activated Protein Kinase Can Regulate Epithelial Cell Proliferation

Gonzales¹,

Haan²,

Baker³

et al. 1999

MBoC

148

105

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Laminin-5 (LN5) is a matrix component of epithelial tissue basement membranes and plays an important role in the initiation and maintenance of epithelial cell anchorage to the underlying connective tissue. Here we show that two distinct LN5 function-inhibitory antibodies, both of which bind the globular domain of the ␣3 subunit, inhibit proliferation of epithelial cells. These same antibodies also induce a decrease in mitogenactivated protein kinase activity. Inhibition of proliferation by the function-perturbing LN5 antibodies is reversed upon removal of the antibodies and can be overcome by providing the antibody-treated cells with exogenous LN5 and rat tail collagen. Because epithelial cells use the integrin receptor ␣3␤1 to interact with both LN5 and rat tail collagen, we next investigated the possibility that integrin ␣3␤1 is involved in mediating the proliferative impact of LN5. Proliferation of human epithelial cells is significantly inhibited by a function-perturbing ␣3 integrin antibody. In addition, antibody activation of ␤1 integrin restores the proliferation of epithelial cells treated with LN5 functionperturbing antibodies. These data indicate that a complex comprising LN5 and ␣3␤1 integrin is multifunctional and contributes not only to epithelial cell adhesion but also to the regulation of cell growth via a signaling pathway involving mitogen-activated protein kinase. We discuss our study in light of recent evidence that LN5 expression is up-regulated at the leading tips of tumors, where it may play a role in tumor cell proliferation. INTRODUCTIONCell interaction with elements of the extracellular matrix impacts their adherence, motility, as well as protein and gene expression (for example, see Adams and Watt, 1993;Roskelly et al., 1995). In intact normal tissue epithelial cells bind to extracellular matrix molecules, which are organized into a complex multiprotein structure called the basement membrane. The major components of the latter include type IV collagen, proteoglycans, and laminins. One laminin isoform, laminin-5 (LN5), 1 in particular plays an important role in establishing firm adherence of epithelial cells to the basement membrane, because it is necessary for the assembly and maintenance of stable anchorage devices between epithelial cells and matrix called hemidesmosomes (Baker et al., 1996;Green and Jones, 1996). However, recent reports also indicate that LN5 is expressed at the budding tips of invading tumor cells, i.e., at sites where cancer cells are undergoing cell division but where there are most likely no hemidesmosomes (Pyke et al., 1994(Pyke et al., , 1995. This provides an indication § Corresponding author. E-mail address: j-jones3@nwu.edu. 1 Abbreviations used: BrdU, bromodeoxyuridine; DAPI, 4,6-diamidino-2-phenylindole; EGF, epidermal growth factor; FN, fibronectin; hLN5, human laminin-5; Ig, immunoglobulin; LN, laminin; MAP, mitogen-activated protein; MAPK, MAP kinase; RTC, rat tail collagen; rtLN5, rat laminin-5.© 1999 by The American Society for Cell Biology 259 that L...

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The role of MCM proteins in the cell cycle control of genome duplication

Cited by 138 publications

References 70 publications

Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5′ end of the lactase gene on chromosome 2q21

Characterisation of a human homologue of a yeast cell division cycle gene, MCM6, located adjacent to the 5′ end of the lactase gene on chromosome 2q21

A DNA Helicase Activity Is Associated with an MCM4, -6, and -7 Protein Complex

A Cell Signal Pathway Involving Laminin-5, α3β1 Integrin, and Mitogen-activated Protein Kinase Can Regulate Epithelial Cell Proliferation

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