Alternative titles; symbols
HGNC Approved Gene Symbol: MCF2
Cytogenetic location: Xq27.1 Genomic coordinates (GRCh38) : X:139,581,770-139,708,167 (from NCBI)
MCF2 is a member of a large family of GDP-GTP exchange factors that modulate the activity of small GTPases of the Rho family. Five-prime recombinations result in the loss of N-terminal codons, producing MCF2 variants with oncogenic potential.
MCF2 is the designation of a transforming sequence identified using cotransfection of DNA from a human mammary carcinoma cell line. Noguchi et al. (1987) cloned this sequence and found that it did not cross-hybridize with the known oncogenes tested.
A comparison of the restriction maps of the DBL and MCF2 oncogenes, together with their chromosomal localization, indicates that they represent the same genetic locus. The DBL oncogene was initially detected as a transforming gene from a human diffuse B-cell lymphoma and was isolated as a 45-kb transforming human DNA sequence by cosmid cloning (Eva and Aaronson, 1985). By molecular hybridization, DBL lacks detectable homology with a large number of cellular or retroviral oncogenes, including members of the tyrosine kinase family. Srivastava et al. (1986) demonstrated that antiserum from mice bearing tumors induced by this oncogene specifically detected a protein of about 66 kD in DBL transformants. Using DBL cDNA, they isolated mRNA from a transfectant clone and found that it directed the in vitro synthesis of this protein. Subcellular localization studies showed that the protein, also known as p66, is a cytoplasmic protein distributed between cytosol and crude membrane fractions. They showed, furthermore, that p66 is a phosphoprotein, with phosphorylation specific to serine residues.
Ron et al. (1988) cloned and characterized the DBL oncogene.
By RT-PCR, Komai et al. (2002) identified 4 splice variants of MCF2: variant 1, which contains 25 exons; variant 2, which contains a 48-bp insertion between exons 10 and 11 and lacks exons 23 and 24; variant 3, which contains the 48-bp insertion and has 3 additional 5-prime exons that replace exon 1; and variant 4, which contains the 48-bp insertion and no other changes. Variant 1 was expressed only in brain; variant 3 was expressed in heart, kidney, spleen, liver, and testis; and variant 4 was expressed in brain, heart, kidney, testis, placenta, stomach, and peripheral blood. Western blot analysis detected several MCF2 species of different molecular masses in brain, heart, kidney, intestine, muscle, lung, and testis.
Ron et al. (1988) showed that overexpression of DBL is sufficient to transform NIH 3T3 cells.
Komai et al. (2002) determined that the 4 splice variants of MCF2 that they identified each displayed unique specificities for modulating the guanine nucleotide exchange activities of the small GTPases RHOA (165390), RAC1 (602048), and CDC42 (116952).
Palmieri et al. (2000) determined that the MCF2 gene contains 25 exons and spans 85 kb. The promoter region contains no consensus TATA or CAAT boxes and no CpG islands. There were simple sequence repeats distributed across the intronic region of the gene. Komai et al. (2002) identified 4 additional exons, 3 of which extend the length of the gene by more than 9 kb in the 5-prime direction.
By in situ hybridization, Noguchi et al. (1987) mapped the MCF2 gene to chromosome Xq27. This localization was confirmed by hybridization to DNA from a panel of human-rodent somatic cell hybrid lines.
By pulsed field gel electrophoresis, Nguyen et al. (1987) found that the MCF2 gene and the F9 gene (300746) are separated by a maximum distance of about 270 kb. Furthermore, they located several HTF islands in this region, i.e., CpG-rich, unmethylated sequences, containing several sites for 'rare cutter' enzymes, which are believed to be associated with expressed 'housekeeping' genes. Anson et al. (1988) further narrowed the interval separating MCF2 and F9, locating MCF2 to a region between 29 and 61 kb 3-prime to F9. Nguyen et al. (1989) concluded from pulsed field gel electrophoresis studies of the Xq27 region that MCF2 is located telomeric to F9.
By in situ hybridization, Tronick et al. (1989) located the DBL gene to Xq27.
By restriction mapping of a YAC clone, Palmieri et al. (2000) mapped the MCF2 gene to chromosome Xq26, about 50 kb telomeric to the F9 gene.
Grant et al. (1990) demonstrated that Mcf-2 in the mouse lies in the same order as the corresponding gene on the human X chromosome: Hprt--Cf-9--Mcf-2--G6pd. In situ hybridization indicated that the gene lies in the same region as Cf-9 and linkage studies in interspecific mouse backcross populations demonstrated that the Cf-9 and Mcf-2 genes were separated by about 0.5 cM.
The DBL oncogene was generated by rearrangements involving 3 discontinuous regions of the human genome. By analysis of DNA from human/rodent somatic cell hybrids, Tronick et al. (1989) demonstrated that the DBL gene located on the X chromosome underwent recombination at its 5-prime and 3-prime ends with sequences derived from chromosomes 3 (pter-p21) and 16 (p13-q22), respectively.
Oncogenic activation of the MCF2 gene occurs through substitution of part of its 5-prime coding region by unrelated nonsyntenic sequences. Galland et al. (1992) demonstrated that the upstream replacing sequence, referred to as URS, represents the farthest 5-prime portion of the locus and that it is derived from the D15S93 locus on human chromosome 15q15-q23.
In 2 unrelated hemophilia B (306900) patients who raised antibodies to infused factor IX, Anson et al. (1988) found deletions in excess of 273 kb encompassing the F9 and MCF2 genes and a CG-rich island. This appeared to be the first reported nullisomic deletion of a transforming gene. No clinical condition could be attributed to the loss of the MCF2 gene. The CG-rich island may be a marker for an as yet undefined gene lying just 5-prime or just 3-prime off the island.
By targeted deletion of the mouse Dbl gene in embryonic stem cells, Hirsch et al. (2002) developed Dbl-null mice. Dbl-null mice were viable and showed normal fertility and no obvious neurologic defects. Examination of mutant testis showed normal morphology, proliferation, and survival of spermatogonia. The brains of Dbl-null mice displayed normal major structures; however, distinct populations of cortical pyramidal neurons contained significantly shortened dendrites, suggesting that Dbl has a role in dendrite elongation.
Anson, D. S., Blake, D. J., Winship, P. R., Birnbaum, D., Brownlee, G. G. Nullisomic deletion of the mcf.2 transforming gene in two haemophilia B patients. EMBO J. 7: 2795-2799, 1988. [PubMed: 2846283] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03134.x]
Eva, A., Aaronson, S. A. Isolation of a new human oncogene from a diffuse B-cell lymphoma. Nature 316: 273-275, 1985. [PubMed: 3875039] [Full Text: https://doi.org/10.1038/316273a0]
Eva, A., Vecchio, G., Rao, C. D., Tronick, S. R., Aaronson, S. A. The predicted DBL oncogene product defines a distinct class of transforming proteins. Proc. Nat. Acad. Sci. 85: 2061-2065, 1988. [PubMed: 3281159] [Full Text: https://doi.org/10.1073/pnas.85.7.2061]
Galland, F., Stefanova, M., Lafage, M., Birnbaum, D. Localization of the 5-prime end of the MCF2 oncogene to human chromosome 15q15-q23. Cytogenet. Cell Genet. 60: 114-116, 1992. [PubMed: 1611909] [Full Text: https://doi.org/10.1159/000133316]
Grant, S. G., Mattei, M.-G., Galland, F., Stephenson, D. A., Keitz, B. T., Birnbaum, D., Chapman, V. M. Localization of the mouse Mcf-2 (Dbl) protooncogene within a conserved linkage group on the mouse X chromosome. Cytogenet. Cell Genet. 54: 175-181, 1990. [PubMed: 2265564] [Full Text: https://doi.org/10.1159/000132988]
Hirsch, E., Pozzato, M., Vercelli, A., Barberis, L., Azzolino, O., Russo, C., Vanni, C., Silengo, L., Eva, A., Altruda, F. Defective dendrite elongation but normal fertility in mice lacking the Rho-like GTPase activator Dbl. Molec. Cell. Biol. 22: 3140-3148, 2002. [PubMed: 11940671] [Full Text: https://doi.org/10.1128/MCB.22.9.3140-3148.2002]
Komai, K., Okayama, R., Kitagawa, M., Yagi, H., Chihara, K., Shiozawa, S. Alternative splicing variants of the human DBL (MCF-2) proto-oncogene. Biochem. Biophys. Res. Commun. 299: 455-458, 2002. [PubMed: 12445822] [Full Text: https://doi.org/10.1016/s0006-291x(02)02645-1]
Nguyen, C., Pontarotti, P., Birnbaum, D., Chimini, G., Rey, J. A., Mattei, J.-F., Jordan, B. R. Large scale physical mapping in the q27 region of the human X chromosome: the coagulation factor IX gene and the mcf.2 transforming sequence are separated by at most 270 kilobase pairs and are surrounded by several 'HTF islands.' EMBO J. 6: 3285-3289, 1987. [PubMed: 2828023] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb02647.x]
Nguyen, C., Poustka, A.-M., Djabali, M., Roux, D., Mattei, J.-F., Lehrach, H., Jordan, B. R. Large-scale mapping and chromosome jumping in the q27 region of the human X chromosome. Genomics 5: 298-303, 1989. [PubMed: 2571578] [Full Text: https://doi.org/10.1016/0888-7543(89)90061-x]
Noguchi, T., Mattei, M.-G., Oberle, I., Planche, J., Imbert, J., Pelassy, C., Birg, F., Birnbaum, D. Localization of the mcf.2 transforming sequence to the X chromosome. EMBO J. 6: 1301-1307, 1987. [PubMed: 3038515] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb02368.x]
Palmieri, G., de Franciscis, V., Casamassimi, A., Romano, G., Torino, A., Pingitore, P., Califano, D., Santelli, G., Eva, A., Vecchio, G., D'Urso, M., Ciccodicola, A. Human dbl proto-oncogene in 85 kb of Xq26, and determination of the transcription initiation site. Gene 253: 107-115, 2000. [PubMed: 10925207] [Full Text: https://doi.org/10.1016/s0378-1119(00)00212-2]
Ron, D., Tronick, S. R., Aaronson, S. A., Eva, A. Molecular cloning and characterization of the human DBL proto-oncogene: evidence that its overexpression is sufficient to transform NIH/3T3 cells. EMBO J. 7: 2465-2473, 1988. [PubMed: 3056717] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03093.x]
Srivastava, S. K., Wheelock, R. H. P., Aaronson, S. A., Eva, A. Identification of the protein encoded by the human diffuse B-cell lymphoma (dbl) oncogene. Proc. Nat. Acad. Sci. 83: 8868-8872, 1986. [PubMed: 3491366] [Full Text: https://doi.org/10.1073/pnas.83.23.8868]
Tronick, S. R., McBride, O. W., Popescu, N. C., Eva, A. Chromosomal localization of DBL oncogene sequences. Genomics 5: 546-553, 1989. [PubMed: 2613238] [Full Text: https://doi.org/10.1016/0888-7543(89)90022-0]