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Gene Review

GMNN  -  geminin, DNA replication inhibitor

Homo sapiens

Synonyms: Gem, Geminin
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Disease relevance of GMNN


High impact information on GMNN


Chemical compound and disease context of GMNN

  • PURPOSE: Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer [7].
  • PATIENTS AND METHODS: In this multicenter phase II trial, patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen received pemetrexed 500 mg/m(2) as a 10-min infusion every 3 weeks until disease progression or occurrence of unacceptable toxicity [8].
  • In two recent randomised trials, gemcitabine plus cisplatin (Gem/Cis) was found to be at least as effective as vinorelbine plus cisplatin (Vin/Cis), paclitaxel plus cisplatin (Pac/Cis), paclitaxel plus carboplatin (Pac/Carbo), or docetaxel plus cisplatin (Doc/Cis) in patients with advanced non-small cell lung cancer (NSCLC) [9].
  • Gemcitabine (Gem) is a deoxycytidine analog that is effective against pancreatic cancer and other malignancies following conversion to the 5'-O-mono-, di- and tri-phosphate forms [10].

Biological context of GMNN

  • Here, we show that inactivation of Geminin, an inhibitor of origin licensing, leads to rereplication in human normal and tumor cells within the same cell cycle [11].
  • These data show that Geminin is required for maintaining genomic stability in human cells [11].
  • Taken together, these findings suggest that Cdt1 function is also negatively regulated by the Cdk phosphorylation independent of geminin binding [12].
  • Geminin was downregulated, whereas cdt1 levels were maintained upon differentiation of both cell lines, independently of whether cells entered extra S-phases [13].
  • Conversely, loss of Gem (in common with gain of Six3 (ref. 1)) promotes retinal precursor-cell proliferation and results in expanded optic vesicles, markedly potentiating Six3 gain-of-function phenotypes [14].

Anatomical context of GMNN

  • Increased expression of geminin stimulates the growth of mammary epithelial cells and is a frequent event in human tumors [3].
  • Moreover, both Cdt1 and Geminin expression are severely downregulated upon differentiation of Caco-2 cells, an in vitro model of intestinal epithelial differentiation [4].
  • In situ hybridization and immunohistochemistry localize Cdt1 as well as geminin to the proliferative compartment of the developing mouse gut epithelium [15].
  • Later, embryos expressing geminin have an expanded dorsal neural territory and ventral ectoderm is converted to neurons [16].
  • Misexpression of geminin in gastrula ectoderm suppresses BMP4 expression and converts prospective epidermis into neural tissue [16].

Associations of GMNN with chemical compounds

  • We show that truncated Geminin produced by cleavage at C1 can promote apoptosis [17].
  • Although Gem expression is rare in epithelial and hematopoietic cancer cell lines, constitutive Gem levels were detected in several neuroblastoma cell lines and could be further induced as much as 10-fold following treatment with PMA or the acetylcholine muscarinic agonist, carbachol [18].
  • Recent evidence indicates that Gemcitabine (Gem) may modulate ERCC1 nucleotide excision repair activity, and down-regulation of DNA repair activity by ERCC1 antisense RNA reportedly inhibits synergism of CDDP/Gem [19].
  • Performance of Gem Premier blood gas/electrolyte analyzer evaluated [20].
  • We have recently shown that Rad and Gem bind calmodulin in a Ca2+-dependent manner via this C-terminal extension, involving residues 278-297 in human Rad. This domain also contains several consensus sites for serine phosphorylation, and Rad is complexed with calmodulin-dependent protein kinase II (CaMKII) in C2C12 cells [21].

Physical interactions of GMNN


Enzymatic interactions of GMNN


Regulatory relationships of GMNN

  • Loss of Geminin induces rereplication in the presence of functional p53 [11].
  • Geminin inhibits cell-cycle progression by sequestering Cdt1 (refs 4, 5), the key component for the assembly of the pre-replication complex [14].
  • It has been described that the replication regulator protein geminin is rapidly degraded at the end of mitosis and newly expressed at the beginning of the next S phase in the metazoan cell cycle [24].
  • Geminin is widely expressed in several malignancies and the number of geminin-expressing cells is directly proportional to the cell proliferation index as measured by Ki-67 expression [25].

Other interactions of GMNN

  • Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint [26].
  • Here we report that geminin forms a parallel coiled-coil homodimer with atypical residues in the dimer interface [27].
  • Cdt1 is rapidly degraded early in S phase, but geminin remains bound to the chromatin sites [28].
  • In this study, we showed that the transcription of human Geminin and Cdt1, as well as that of MCM7, is activated by transcription factors E2F1-4, but not by factors E2F5-7 [29].
  • Licensing is blocked at other cell cycle stages by the activity of cyclin-dependent kinases and a small protein called geminin [30].

Analytical, diagnostic and therapeutic context of GMNN


  1. Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1. Karakaidos, P., Taraviras, S., Vassiliou, L.V., Zacharatos, P., Kastrinakis, N.G., Kougiou, D., Kouloukoussa, M., Nishitani, H., Papavassiliou, A.G., Lygerou, Z., Gorgoulis, V.G. Am. J. Pathol. (2004) [Pubmed]
  2. Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication. Biswas, N., Sanchez, V., Spector, D.H. J. Virol. (2003) [Pubmed]
  3. Increased expression of geminin stimulates the growth of mammary epithelial cells and is a frequent event in human tumors. Montanari, M., Boninsegna, A., Faraglia, B., Coco, C., Giordano, A., Cittadini, A., Sgambato, A. J. Cell. Physiol. (2005) [Pubmed]
  4. Expression of the licensing factors, Cdt1 and Geminin, in human colon cancer. Bravou, V., Nishitani, H., Song, S.Y., Taraviras, S., Varakis, J. Int. J. Oncol. (2005) [Pubmed]
  5. Geminin, an inhibitor of DNA replication, is degraded during mitosis. McGarry, T.J., Kirschner, M.W. Cell (1998) [Pubmed]
  6. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Wohlschlegel, J.A., Dwyer, B.T., Dhar, S.K., Cvetic, C., Walter, J.C., Dutta, A. Science (2000) [Pubmed]
  7. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. Louvet, C., Labianca, R., Hammel, P., Lledo, G., Zampino, M.G., André, T., Zaniboni, A., Ducreux, M., Aitini, E., Taïeb, J., Faroux, R., Lepere, C., de Gramont, A. J. Clin. Oncol. (2005) [Pubmed]
  8. Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial. Boeck, S., Weigang-Köhler, K., Fuchs, M., Kettner, E., Quietzsch, D., Trojan, J., Stötzer, O., Zeuzem, S., Lordick, F., Köhne, C.H., Kröning, H., Steinmetz, T., Depenbrock, H., Heinemann, V. Ann. Oncol. (2007) [Pubmed]
  9. Retrospective cost analysis of gemcitabine in combination with cisplatin in non-small cell lung cancer compared to other combination therapies in Europe. Schiller, J., Tilden, D., Aristides, M., Lees, M., Kielhorn, A., Maniadakis, N., Bhalla, S. Lung Cancer (2004) [Pubmed]
  10. Antineoplastic activity of a novel multimeric gemcitabine-monophosphate prodrug against thyroid cancer cells in vitro. Kotchetkov, R., Gröschel, B., Gmeiner, W.H., Krivtchik, A.A., Trump, E., Bitoova, M., Cinatl, J., Kornhuber, B., Cinatl, J. Anticancer Res. (2000) [Pubmed]
  11. Loss of Geminin induces rereplication in the presence of functional p53. Melixetian, M., Ballabeni, A., Masiero, L., Gasparini, P., Zamponi, R., Bartek, J., Lukas, J., Helin, K. J. Cell Biol. (2004) [Pubmed]
  12. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. Sugimoto, N., Tatsumi, Y., Tsurumi, T., Matsukage, A., Kiyono, T., Nishitani, H., Fujita, M. J. Biol. Chem. (2004) [Pubmed]
  13. Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization. Bermejo, R., Vilaboa, N., Calés, C. Mol. Biol. Cell (2002) [Pubmed]
  14. Direct interaction of geminin and Six3 in eye development. Del Bene, F., Tessmar-Raible, K., Wittbrodt, J. Nature (2004) [Pubmed]
  15. Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. Xouri, G., Lygerou, Z., Nishitani, H., Pachnis, V., Nurse, P., Taraviras, S. Eur. J. Biochem. (2004) [Pubmed]
  16. Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation. Kroll, K.L., Salic, A.N., Evans, L.M., Kirschner, M.W. Development (1998) [Pubmed]
  17. Geminin Cleavage during Apoptosis by Caspase-3 Alters Its Binding Ability to the SWI/SNF Subunit Brahma. Roukos, V., Iliou, M.S., Nishitani, H., Gentzel, M., Wilm, M., Taraviras, S., Lygerou, Z. J. Biol. Chem. (2007) [Pubmed]
  18. The Gem GTP-binding protein promotes morphological differentiation in neuroblastoma. Leone, A., Mitsiades, N., Ward, Y., Spinelli, B., Poulaki, V., Tsokos, M., Kelly, K. Oncogene (2001) [Pubmed]
  19. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Lord, R.V., Brabender, J., Gandara, D., Alberola, V., Camps, C., Domine, M., Cardenal, F., Sánchez, J.M., Gumerlock, P.H., Tarón, M., Sánchez, J.J., Danenberg, K.D., Danenberg, P.V., Rosell, R. Clin. Cancer Res. (2002) [Pubmed]
  20. Performance of Gem Premier blood gas/electrolyte analyzer evaluated. Jacobs, E., Nowakowski, M., Colman, N. Clin. Chem. (1993) [Pubmed]
  21. Effects of phosphorylation on function of the Rad GTPase. Moyers, J.S., Zhu, J., Kahn, C.R. Biochem. J. (1998) [Pubmed]
  22. The regulation of embryonic patterning and DNA replication by geminin. Pitulescu, M., Kessel, M., Luo, L. Cell. Mol. Life Sci. (2005) [Pubmed]
  23. Cdt1 associates dynamically with chromatin throughout G1 and recruits Geminin onto chromatin. Xouri, G., Squire, A., Dimaki, M., Geverts, B., Verveer, P.J., Taraviras, S., Nishitani, H., Houtsmuller, A.B., Bastiaens, P.I., Lygerou, Z. EMBO J. (2007) [Pubmed]
  24. Expression and phosphorylation of the replication regulator protein geminin. Kulartz, M., Kreitz, S., Hiller, E., Damoc, E.C., Przybylski, M., Knippers, R. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  25. Expression of geminin as a marker of cell proliferation in normal tissues and malignancies. Wohlschlegel, J.A., Kutok, J.L., Weng, A.P., Dutta, A. Am. J. Pathol. (2002) [Pubmed]
  26. Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint. Zhu, W., Chen, Y., Dutta, A. Mol. Cell. Biol. (2004) [Pubmed]
  27. A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition. Saxena, S., Yuan, P., Dhar, S.K., Senga, T., Takeda, D., Robinson, H., Kornbluth, S., Swaminathan, K., Dutta, A. Mol. Cell (2004) [Pubmed]
  28. The replicative regulator protein geminin on chromatin in the HeLa cell cycle. Kulartz, M., Knippers, R. J. Biol. Chem. (2004) [Pubmed]
  29. Regulation of Geminin and Cdt1 expression by E2F transcription factors. Yoshida, K., Inoue, I. Oncogene (2004) [Pubmed]
  30. Cell type-specific responses of human cells to inhibition of replication licensing. Shreeram, S., Sparks, A., Lane, D.P., Blow, J.J. Oncogene (2002) [Pubmed]
  31. Subcellular translocation signals regulate Geminin activity during embryonic development. Boos, A., Lee, A., Thompson, D.M., Kroll, K.L. Biol. Cell (2006) [Pubmed]
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