Cyclin A Is Redundant in Fibroblasts but Essential in Hematopoietic and Embryonic Stem Cells
Open accessAbstract
Cyclins are regulatory subunits of cyclin-dependent kinases. Cyclin A, the first cyclin ever cloned, is thought to be an essential component of the cell-cycle engine. Mammalian cells encode two A-type cyclins, testis-specific cyclin A1 and ubiquitously expressed cyclin A2. Here, we tested the requirement for cyclin A function using conditional knockout mice lacking both A-type cyclins. We found that acute ablation of cyclin A in fibroblasts did not affect cell proliferation, but led to prolonged expression of another cyclin, cyclin E, across the cell cycle. However, combined ablation of all A- and E-type cyclins extinguished cell division. In contrast, cyclin A function was essential for cell-cycle progression of hematopoietic and embryonic stem cells. Expression of cyclin A is particularly high in these compartments, which might render stem cells dependent on cyclin A, whereas in fibroblasts cyclins A and E play redundant roles in cell proliferation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HSCs lacking cyclin A2 cannot proliferate in vitro, indicating cyclin A2 is essential for HSC proliferation.
“HSCs that lack cyclin A2 are unable to proliferate in vitro, indicating the essential role of cyclin A2 in HSC proliferation48.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [48]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cell cycle, CDKs and cancer: a changing paradigm
Malumbres, M., & Barbacid, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2602 · Cited by 3,957 · cited 1× · see citing works
“In contrast, mice lacking particular G1 cyclins or Cdks displayed normal proliferation in the overwhelming majority of cell types and presented only narrow, tissue-specific abnormalities (Sherr and Roberts, 2004; Li et al., 2009; Malumbres and Barbacid, 2009).”
BackgroundA clonogenic common myeloid progenitor that gives rise to all myeloid lineages
Akashi, K., Traver, D., Miyamoto, T., & Weissman, I. L. (2000) · Nature · doi:10.1038/35004599 · Cited by 2,617 · see citing works
Self-citationInducible Gene Targeting in Mice
Kühn, R., Schwenk, F., Aguet, M., & Rajewsky, K. (1995) · Science · doi:10.1126/science.7660125 · Cited by 1,915 · see citing works
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871 · see citing works
Evans, T., Rosenthal, E. T., Youngblom, J., Distel, D. L., & Hunt, T. (1983) · Cell · doi:10.1016/0092-8674(83)90420-8 · Cited by 1,516 · see citing works
Cyclin A is required at two points in the human cell cycle.
Pagano, M., Pepperkok, R., Verde, F., Ansorge, W. J., & Draetta, G. F. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05135.x · Cited by 1,403 · see citing works
Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation
Molofsky, A. V., Pardal, R., Iwashita, T., Park, I.-K., Clarke, M. F., & Morrison, S. J. (2003) · Nature · doi:10.1038/nature02060 · Cited by 1,301 · see citing works
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106 · see citing works
Living with or without cyclins and cyclin-dependent kinases
Sherr, C. J., & Roberts, J. M. (2004) · Genes & Development · doi:10.1101/gad.1256504 · Cited by 1,089 · see citing works
p16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003 · cited 2× · see citing works
“…increased p16INK4a levels during aging contribute to agedependent decline in regenerative capacity of pancreatic islet cells, neural stem cells, and hematopoietic stem cells, while ablation of p16INK4a reversed these changes (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006).”
BackgroundResultIncreasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature05091 · Cited by 972 · cited 2× · see citing works
“…increased p16INK4a levels during aging contribute to agedependent decline in regenerative capacity of pancreatic islet cells, neural stem cells, and hematopoietic stem cells, while ablation of p16INK4a reversed these changes (Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006).”
BackgroundResultCyclin a is required for the onset of DNA replication in mammalian fibroblasts
Girard, F., Strausfeld, U. P., Fernandez, A., & Lamb, N. J. C. (1991) · Cell · doi:10.1016/0092-8674(91)90293-8 · Cited by 880 · see citing works
Wnt signaling and stem cell control
Nusse, R. (2008) · Cell Research · doi:10.1038/cr.2008.47 · Cited by 847 · see citing works
Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B
Pines, J., & Hunter, T. R. (1990) · Nature · doi:10.1038/346760a0 · Cited by 716 · see citing works
Cyclin E Ablation in the Mouse
Geng, Y., Yu, Q., Sicińska, E., Das, M., Schneider, J. E., Bhattacharya, S., Rideout, W. M., Bronson, R. T., Gardner, H., & Siciński, P. (2003) · Cell · doi:10.1016/s0092-8674(03)00645-7 · Cited by 663 · see citing works
Self-citationMouse development and cell proliferation in the absence of D-cyclins
Kozar, K., Ciemerych, M. A., Rebel, V. I., Shigematsu, H., Zagozdzon, A., Sicinska, E., Geng, Y., Yu, Q., Bhattacharya, S., Bronson, R. T., et al. (2004) · Cell · doi:10.1016/j.cell.2004.07.025 · Cited by 647 · see citing works
Self-citationEggan, K. C., Akutsu, H., Loring, J. M., Jackson‐Grusby, L., Klemm, M., Rideout, W. M., Yanagimachi, R., & Jaenisch, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.101118898 · Cited by 613 · see citing works
The purification and characterization of fetal liver hematopoietic stem cells
Morrison, S. J., Hemmati, H. D., Wandycz, A. M., & Weissman, I. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.22.10302 · Cited by 611 · see citing works
Cyclin-dependent kinases and cell-cycle transitions: does one fit all?
Hochegger, H., Takeda, S., & Hunt, T. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2510 · Cited by 599 · see citing works
Swenson, K. I., Farrell, K. M., & RUDERMAN, J. V. (1986) · Cell · doi:10.1016/0092-8674(86)90801-9 · Cited by 535 · see citing works
Cyclin A in cell cycle control and cancer
Yam, C. H., Fung, T. K., & Poon, R. Y. C. (2002) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-002-8510-y · Cited by 520 · see citing works
Geley, S., Kramer, E., Gieffers, C., Gannon, J., Peters, J., & Hunt, T. (2001) · Journal of Cell Biology · doi:10.1083/jcb.153.1.137 · Cited by 462 · see citing works
The roles of Drosophila cyclins A and B in mitotic control
Lehner, C. F., & O’Farrell, P. H. (1990) · Cell · doi:10.1016/0092-8674(90)90535-m · Cited by 435 · see citing works
Expression and function of Drosophila cyclin a during embryonic cell cycle progression
Lehner, C. F., & O’Farrell, P. H. (1989) · Cell · doi:10.1016/0092-8674(89)90629-6 · Cited by 398 · see citing works
Cyclin a Is Destroyed in Prometaphase and Can Delay Chromosome Alignment and Anaphase
den Elzen, N. R., & Pines, J. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.1.121 · Cited by 372 · see citing works
Cyclin A1 is required for meiosis in the male mouse
Liu, D., Matzuk, M. M., Sung, W. K., et al. (1998) · Nature Genetics · doi:10.1038/3855 · Cited by 372 · see citing works
Differential modulation of cyclin gene expression by MYC.
Jansen‐Dürr, P., Meichle, A., Steiner, P., Pagano, M., Finke, K., Botz, J. W., Wessbecher, J., Draetta, G. F., & Eilers, M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3685 · Cited by 310 · see citing works
Silver, D. P., & Livingston, D. M. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00295-7 · Cited by 293 · see citing works
Self-citationDelayed early embryonic lethality following disruption of the murine cyclin A2 gene
Murphy, M., Stinnakre, M., Sénamaud‐Beaufort, C., Winston, N. J., Sweeney, C., Kubelka, M., Carrington, M., Bréchot, C., & Sobczak‐Thépot, J. (1997) · Nature Genetics · doi:10.1038/ng0197-83 · Cited by 279 · see citing works
Cyclin A is required in S phase in normal epithelial cells
Zindy, F., Lamas, E., Chenivesse, X., Sobczak‐Thépot, J., Wang, J., Fesquet, D., Henglein, B., & Bréchot, C. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(92)91851-g · Cited by 271 · see citing works
Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells
Parisi, T., Beck, A. R., Rougier, N., McNeil, T., Lucian, L. A., Werb, Z., & Amati, B. B. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg482 · Cited by 264 · see citing works
Human Cyclin a Is Required for Mitosis until Mid Prophase
Furuno, N., den Elzen, N. R., & Pines, J. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.147.2.295 · Cited by 254 · see citing works
A distinct cyclin A is expressed in germ cells in the mouse
Sweeney, C., Murphy, M. J., Kubelka, M., et al. (1996) · Development · doi:10.1242/dev.122.1.53 · Cited by 218 · see citing works
Kinase-independent function of cyclin E
Geng, Y., Lee, Y.-M., Welcker, M., Swanger, J., Zagozdzon, A., Winer, J. D., Roberts, J. M., Kaldis, P., Clurman, B. E., & Sicinski, P. (2007) · Molecular Cell · doi:10.1016/j.molcel.2006.11.029 · Cited by 187 · see citing works
Self-citationCaMKII?-cre transgene expression and recombination patterns in the mouse brain
Dragatsis, I., & Zeitlin, S. O. (2000) · genesis · doi:10.1002/(sici)1526-968x(200002)26:2 · Cited by 171 · see citing works
Cyclin A2 Regulates Nuclear-Envelope Breakdown and the Nuclear Accumulation of Cyclin B1
Gong, D., Pomerening, J. R., Myers, J. W., Gustavsson, C., Jones, J. T., Hahn, A. T., Meyer, T., & Ferrell, J. E. (2007) · Current Biology · doi:10.1016/j.cub.2006.11.066 · Cited by 151 · see citing works
Yang, R., Roberta Morosetti, A., & Koeffler, H. P. (1997) · PubMed · Cited by 137 · see citing works
Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction and Prevents Heart Failure
Cheng, R. K.-H., Asai, T., Tang, H., Dashoush, N. H., Kara, R. J., Costa, K. D., Naka, Y., Wu, E. X., Wolgemuth, D. J., & Chaudhry, H. W. (2007) · Circulation Research · doi:10.1161/circresaha.107.153544 · Cited by 128 · see citing works
Self-citationAccumulation of Cyclin E Is Not a Prerequisite for Passage through the Restriction Point
Ekholm, S. V., Zickert, P., Reed, S. I., & Zetterberg, A. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.9.3256-3265.2001 · Cited by 99 · see citing works
Ji, P., Agrawal, S., Diederichs, S., et al. (2004) · Oncogene · doi:10.1038/sj.onc.1208356 · Cited by 96 · see citing works
A Detailed Analysis of Cyclin A Accumulation at the G1/S Border in Normal and Transformed Cells
Erlandsson, F., Linnman, C., Ekholm, S. V., Bengtsson, E. W., & Zetterberg, A. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4889 · Cited by 76 · see citing works
Cyclin a but not cyclin D1 is essential for c‐myc‐modulated cell‐cycle progression
Qi, Y., Tu, Y., Yang, D., et al. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20816 · Cited by 55 · see citing works
Cyclin A Links c-Myc to Adhesion-independent Cell Proliferation
Barrett, J. F., Lewis, B. C., Hoang, A. T., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.27.15923 · Cited by 52 · see citing works
Whole-genome analysis of animal A- and B-type cyclins
Nieduszynski, C. A., Murray, J. A. H., & Carrington, M. (2002) · Genome biology · doi:10.1186/gb-2002-3-12-research0070 · Cited by 51 · see citing works
Cyclin A1 protein shows haplo-insufficiency for normal fertility in male mice
van der Meer, T., Chan, W.-Y. I., Palazón, L. S., et al. (2004) · Reproduction · doi:10.1530/rep.1.00131 · Cited by 35 · see citing works
C/EBPα Is Required for Proteolytic Cleavage of Cyclin A by Calpain 3 in Myeloid Precursor Cells
Welm, A. L., Timchenko, N. A., Ono, Y., Sorimachi, H., Radomska, H. S., Tenen, D. G., Lekstrom-Himes, J. A., & Darlington, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204096200 · Cited by 28 · see citing works
Yang, J., & Krauss, R. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.5.3103 · Cited by 24 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Guadagno TM Ohtsubo M Roberts JM Assoian RK A link between cyclin A expression and adhesion-dependent cell cycle progression [published erratum appears in Science 1994 Jan 28; 263(5146):455] Science 1993 262 1572 1575 8248807
Cited by
Sorted by citations
Molecular regulation of stem cell quiescence
Cheung, T. H., & Rando, T. A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3591 · Cited by 1,148 · see citing works
Barr, A. R., Cooper, S., Heldt, F. S., Butera, F., Stoy, H., Mansfeld, J., Novák, B., & Bakal, C. (2017) · Nature Communications · doi:10.1038/ncomms14728 · Cited by 403 · see citing works
The Requirement for Cyclin D Function in Tumor Maintenance
Choi, Y. J., Li, X., Hydbring, P., Sanda, T., Stefano, J., Christie, A. L., Signoretti, S., Look, A. T., Kung, A. L., von Boehmer, H., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.09.015 · Cited by 342 · see citing works
Self-citationp57 is required for quiescence and maintenance of adult hematopoietic stem cells
Matsumoto, A., Takeishi, S., Kanie, T., Susaki, E., Onoyama, I., Tateishi, Y., Nakayama, K., & Nakayama, K. I. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.06.014 · Cited by 329 · see citing works
Canonical and atypical E2Fs regulate the mammalian endocycle
Chen, H.-Z., Ouseph, M. M., Li, J., Pécot, T., Chokshi, V., Kent, L., Bae, S., Byrne, M., Duran, C., Comstock, G., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2595 · Cited by 161 · see citing works
Self-citationLoss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis.
Gopinathan, L., Tan, S. L. W., Padmakumar, V. C., Coppola, V., Tessarollo, L., & Kaldis, P. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3440 · Cited by 123 · see citing works
PPP2R5A: A multirole protein phosphatase subunit in regulating cancer development
Mao, Z., Liu, C., Lin, X., Sun, B., & Su, C. (2018) · Cancer Letters · doi:10.1016/j.canlet.2017.11.024 · Cited by 30 · see citing works
- Authors
- Kalaszczynska, I., Geng, Y., Iino, T., Mizuno, S.-I., Choi, Y., Kondratiuk, I., Silver, D. P., Wolgemuth, D. J., Akashi, K., & Sicinski, P.
- Affiliations
- Harvard University (US)
- Columbia University Irving Medical Center (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 138
- Issue
- 2
- Pages
- 352-365
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2745999
- OpenAlex
- W2039543791
- Cited by
- 215
- References
- 47
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 17 · 2020: 12 · 2019: 9 · 2018: 12 · 2017: 15 · 2016: 12 · 2015: 12 · 2014: 13 · 2013: 19 · 2012: 29
- FWCI
- 10.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1477 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA132740, R01CA108950)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD034915)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- cyclin A, cyclin A1, cyclin A2, cyclin E, cyclin-dependent kinases, cell cycle, fibroblasts, hematopoietic stem cells, embryonic stem cells, conditional knockout mice, cell proliferation, functional redundancy
- MeSH terms
- Animals, Embryo, Mammalian, Fibroblasts, Hematopoietic Stem Cells, Mice, Knockout, Cyclin A, Cyclin E, Mice, Embryonic Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
