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Gene Review

Ccna2  -  cyclin A2

Mus musculus

Synonyms: AA408589, Ccn-1, Ccn1, Ccna, CycA2, ...
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Disease relevance of Ccna2


High impact information on Ccna2

  • Surprisingly, homozygous null mutant embryos develop normally until post-implantation, around day 5.5 p.c. This observation may be explained by the persistence of a maternal pool of cyclin A2 protein until at least the blastocyst stage, or an unexpected role for cyclin A1 during early embryo development [6].
  • To address the possible redundancy between different cyclins in vivo and also the control of early embryonic cell cycles, we undertook the targeted deletion of the murine cyclin A2 gene [6].
  • In contrast, overexpression of cyclin A2 appears to advance S phase entry and confer anchorage-independent growth, and can lead to apoptosis [6].
  • Here, we show that suppression of E2F-1 DNA-binding activity by cyclin A-kinase is linked to orderly S phase progression [7].
  • The release of E2F from the cyclin A complex coincides with the stimulation of an E2F-dependent promoter [8].

Chemical compound and disease context of Ccna2


Biological context of Ccna2


Anatomical context of Ccna2

  • Cyclin A2 complexes were active in primary mouse embryonic fibroblasts (MEFs), embryo extracts and in spleen extracts from young animals [13].
  • Accelerated cell cycle progression in osteoblasts overexpressing the c-fos proto-oncogene: induction of cyclin A and enhanced CDK2 activity [12].
  • By contrast, cyclin A2 was expressed in spermatogonia and was most abundant in preleptotene spermatocytes, cells which will enter the meiotic pathway [14].
  • Cyclin A2 hearts demonstrated increased borderzone myofilament density (39.8+/-1.1 versus 31.8+/-1.0 cells/hpf; P=0.0011) [15].
  • Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage [16].

Associations of Ccna2 with chemical compounds

  • This cyclin A2 may be generated from maternally recruited cyclin A2 mRNA because its accumulation was inhibited by 3'-deoxyadenosine, which inhibits mRNA polyadenylation [17].
  • Consistent with this observation, PCNA immunoreactivity and cyclin A protein expression were also increased with bortezomib treatment [18].
  • Taken together, these results suggest that v-Abl tyrosine kinase arrests cell cycle progression in G1 by inhibiting the expression of cyclin A [19].
  • Administration of dexamethasone at this, but not earlier stages, results in reduction of cyclin A and CDK2 levels with a parallel decrease in the associated kinase activity, dissociation of cyclin A-CDK2 from the E2F4-p130 complexes, and inhibition of G(1)/S transition [20].
  • In addition, a significant content reduction of cyclin D1/cdk4 and cyclin A/cdk2 complexes was found after TGF-beta1 inhibition of MPA-dependent and -independent proliferation [21].
  • Our results demonstrate that nuclear PtdIns(4,5)P2 down-regulation caused a delay in phorbol ester-induced S phase entry and that this was at least in part channeled through cyclin A2 at the transcriptional level [22].

Physical interactions of Ccna2


Regulatory relationships of Ccna2

  • The truncated cyclin A2 binds to and activates the cyclin-dependent kinase 2 (CDK2) [26].
  • We show that loss of cell adhesion to substratum abrogates cyclin A gene expression by blocking its promoter activity through the E2F site that mediates its cell cycle regulation in adherent cells [23].
  • These results suggest that E2F1 and cyclin A2 may be induced by c-Myc to mediate the onset of mammary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression [27].
  • As reported here, TGF beta 1 significantly inhibited mRNA expression of B-myb and cyclin A in both cell lines, suggesting that these may be important common downstream targets in the growth inhibition pathway [28].
  • Also, the dominant negative forms of Ras, MAPK, and JNK strongly inhibited Galpha12(R203C)-induced stimulation of cyclin A promoter activity [29].

Other interactions of Ccna2

  • Our results indicate that the distinct mitogenic activities of PDGF and PPP differentially influence the activation of cyclin E- and cyclin A-associated kinases that ultimately regulate entry into S phase [30].
  • The early increase in cyclin D1 protein levels was associated with a faster onset of increased expression of S-phase-associated cyclin A (24 hours versus 36 hours with PH mice) [31].
  • Treatment of early G1 cells with anti-IgM prevented this increase in cyclin A-associated kinase activity at late G1, despite minimal changes in the overall level of cyclin A and Cdk2 proteins [2].
  • Whereas Fgf2 RNA is undetectable in tumors, CcnA2 RNA and cyclin A2 protein was overexpressed in 25 and 50% of tumors, respectively [32].
  • TNF-alpha mRNA levels were significantly elevated in the hippocampus by 12 h and remained elevated for 72 h. mRNA levels for cyclin A2 and cyclin B1 were elevated by approximately 2-fold at 72 h [16].

Analytical, diagnostic and therapeutic context of Ccna2


  1. Cyclin A activates the DNA polymerase delta -dependent elongation machinery in vitro: A parvovirus DNA replication model. Bashir, T., Horlein, R., Rommelaere, J., Willwand, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  2. Role of cyclin A and p27 in anti-IgM induced G1 growth arrest of murine B-cell lymphomas. Ezhevsky, S.A., Toyoshima, H., Hunter, T., Scott, D.W. Mol. Biol. Cell (1996) [Pubmed]
  3. Hexamethylenebisacetamide-induced erythroleukemia cell differentiation involves modulation of events required for cell cycle progression through G1. Kiyokawa, H., Richon, V.M., Venta-Perez, G., Rifkind, R.A., Marks, P.A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  4. Expression of E1A in terminally differentiated muscle cells reactivates the cell cycle and suppresses tissue-specific genes by separable mechanisms. Tiainen, M., Spitkovsky, D., Jansen-Dürr, P., Sacchi, A., Crescenzi, M. Mol. Cell. Biol. (1996) [Pubmed]
  5. Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic myocardium. Chaudhry, H.W., Dashoush, N.H., Tang, H., Zhang, L., Wang, X., Wu, E.X., Wolgemuth, D.J. J. Biol. Chem. (2004) [Pubmed]
  6. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Murphy, M., Stinnakre, M.G., Senamaud-Beaufort, C., Winston, N.J., Sweeney, C., Kubelka, M., Carrington, M., Bréchot, C., Sobczak-Thépot, J. Nat. Genet. (1997) [Pubmed]
  7. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Krek, W., Xu, G., Livingston, D.M. Cell (1995) [Pubmed]
  8. Cell cycle regulation of the E2F transcription factor involves an interaction with cyclin A. Mudryj, M., Devoto, S.H., Hiebert, S.W., Hunter, T., Pines, J., Nevins, J.R. Cell (1991) [Pubmed]
  9. Cyclin-dependent kinase 2 and cyclin A interaction with E2F are targets for tyrosine induction of B16 melanoma terminal differentiation. Rieber, M., Rieber, M.S. Cell Growth Differ. (1994) [Pubmed]
  10. Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Schulze, A., Zerfass, K., Spitkovsky, D., Middendorp, S., Bergès, J., Helin, K., Jansen-Dürr, P., Henglein, B. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  11. Role for Brm in cell growth control. Coisy-Quivy, M., Disson, O., Roure, V., Muchardt, C., Blanchard, J.M., Dantonel, J.C. Cancer Res. (2006) [Pubmed]
  12. Accelerated cell cycle progression in osteoblasts overexpressing the c-fos proto-oncogene: induction of cyclin A and enhanced CDK2 activity. Sunters, A., Thomas, D.P., Yeudall, W.A., Grigoriadis, A.E. J. Biol. Chem. (2004) [Pubmed]
  13. Cdk2 knockout mice are viable. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L., Kaldis, P. Curr. Biol. (2003) [Pubmed]
  14. Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage. Ravnik, S.E., Wolgemuth, D.J. Dev. Biol. (1999) [Pubmed]
  15. Therapeutic delivery of cyclin A2 induces myocardial regeneration and enhances cardiac function in ischemic heart failure. Woo, Y.J., Panlilio, C.M., Cheng, R.K., Liao, G.P., Atluri, P., Hsu, V.M., Cohen, J.E., Chaudhry, H.W. Circulation (2006) [Pubmed]
  16. Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage. McPherson, C.A., Kubik, J., Wine, R.N., D'Hellencourt, C.L., Harry, G.J. Neurotoxicity research. (2003) [Pubmed]
  17. Cyclin A2-CDK2 regulates embryonic gene activation in 1-cell mouse embryos. Hara, K.T., Oda, S., Naito, K., Nagata, M., Schultz, R.M., Aoki, F. Dev. Biol. (2005) [Pubmed]
  18. Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse. Anan, A., Baskin-Bey, E.S., Isomoto, H., Mott, J.L., Bronk, S.F., Albrecht, J.H., Gores, G.J. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  19. Cells arrested in G1 by the v-Abl tyrosine kinase do not express cyclin A despite the hyperphosphorylation of RB. Chen, Y., Knudsen, E.S., Wang, J.Y. J. Biol. Chem. (1996) [Pubmed]
  20. Glucocorticoids inhibit developmental stage-specific osteoblast cell cycle. Dissociation of cyclin A-cyclin-dependent kinase 2 from E2F4-p130 complexes. Smith, E., Redman, R.A., Logg, C.R., Coetzee, G.A., Kasahara, N., Frenkel, B. J. Biol. Chem. (2000) [Pubmed]
  21. Mechanisms of cell cycle arrest in response to TGF-beta in progestin-dependent and -independent growth of mammary tumors. Salatino, M., Labriola, L., Schillaci, R., Charreau, E.H., Elizalde, P.V. Exp. Cell Res. (2001) [Pubmed]
  22. Identification of cyclin A2 as the downstream effector of the nuclear phosphatidylinositol 4,5-bisphosphate signaling network. Ho, K.K., Anderson, A.A., Rosivatz, E., Lam, E.W., Woscholski, R., Mann, D.J. J. Biol. Chem. (2008) [Pubmed]
  23. Anchorage-dependent transcription of the cyclin A gene. Schulze, A., Zerfass-Thome, K., Bergès, J., Middendorp, S., Jansen-Dürr, P., Henglein, B. Mol. Cell. Biol. (1996) [Pubmed]
  24. The DP-1 transcription factor is required for keratinocyte growth and epidermal stratification. Chang, W.Y., Bryce, D.M., D'Souza, S.J., Dagnino, L. J. Biol. Chem. (2004) [Pubmed]
  25. Regulation of E2F/cyclin A-containing complex upon retinoic acid-induced differentiation of teratocarcinoma cells. Reichel, R.R. Gene Expr. (1992) [Pubmed]
  26. The appearance of truncated cyclin A2 correlates with differentiation of mouse embryonic stem cells. Anger, M., Bryja, V., Jirmanova, L., Hampl, A., Carrington, M., Motlik, J., Dvorak, P., Kubelka, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  27. Cell cycle basis for the onset and progression of c-Myc-induced, TGFalpha-enhanced mouse mammary gland carcinogenesis. Liao, D.J., Natarajan, G., Deming, S.L., Jamerson, M.H., Johnson, M., Chepko, G., Dickson, R.B. Oncogene (2000) [Pubmed]
  28. Inhibition of cell growth by TGF beta 1 is associated with inhibition of B-myb and cyclin A in both BALB/MK and Mv1Lu cells. Satterwhite, D.J., Aakre, M.E., Gorska, A.E., Moses, H.L. Cell Growth Differ. (1994) [Pubmed]
  29. Dependence of activated Galpha12-induced G1 to S phase cell cycle progression on both Ras/mitogen-activated protein kinase and Ras/Rac1/Jun N-terminal kinase cascades in NIH3T3 fibroblasts. Mitsui, H., Takuwa, N., Kurokawa, K., Exton, J.H., Takuwa, Y. J. Biol. Chem. (1997) [Pubmed]
  30. Differential modulation of G1 cyclins and the Cdk inhibitor p27kip1 by platelet-derived growth factor and plasma factors in density-arrested fibroblasts. Winston, J., Dong, F., Pledger, W.J. J. Biol. Chem. (1996) [Pubmed]
  31. Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-Bis[2-(3,5-Dichloropyridyloxy)] benzene. Ledda-Columbano, G.M., Pibiri, M., Loi, R., Perra, A., Shinozuka, H., Columbano, A. Am. J. Pathol. (2000) [Pubmed]
  32. Restriction landmark genomic scanning of mouse liver tumors for gene amplification: overexpression of cyclin A2. Haddad, R., Morrow, A.D., Plass, C., Held, W.A. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  33. Cell cycle regulatory proteins in the liver in murine Trypanosoma cruzi infection. Bouzahzah, B., Nagajyothi, F., Desruisseaux, M.S., Krishnamachary, M., Factor, S.M., Cohen, A.W., Lisanti, M.P., Petkova, S.B., Pestell, R.G., Wittner, M., Mukherjee, S., Weiss, L.M., Jelicks, L.A., Albanese, C., Tanowitz, H.B. Cell Cycle (2006) [Pubmed]
  34. Regulation of cyclin and cyclin-dependent kinase gene expression during lens differentiation requires the retinoblastoma protein. Fromm, L., Overbeek, P.A. Oncogene (1996) [Pubmed]
  35. Distinct roles for the mammalian A-type cyclins during oogenesis. Persson, J.L., Zhang, Q., Wang, X.Y., Ravnik, S.E., Muhlrad, S., Wolgemuth, D.J. Reproduction (2005) [Pubmed]
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