Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Connecting proliferation and apoptosis in development and disease

Nature Reviews Molecular Cell Biology volume 5, pages 805–815 (2004)Cite this article

Key Points

  • Signals that trigger cell proliferation also trigger programmed cell death. This functions as a protective mechanism against cancer. Control of proliferation-induced cell death is also essential to permit normal tissue growth during development.

  • The Myc proteins have a central role in controlling cell and tissue growth in animals. Myc mutant animals are small.

  • In multicellular tissues, cells compete with one another for growth and survival cues. Myc activity affects the ability of cells to compete. Evidence has begun to accumulate that cell competition has an important role in the control of tissue growth during Drosophila melanogaster development. At present, nothing is known about whether competition has a comparable role in vertebrate development, although this seems likely.

  • Genetic screens for loci affecting tissue growth in D. melanogaster have identified new genes that simultaneously promote proliferation and inhibit apoptosis (or vice versa). Mutations in several of the mammalian orthologues have been linked to specific cancers.

Abstract

Cells grow and divide rapidly during embryonic and postnatal development. Net tissue growth reflects the balance between the addition of new cells and the elimination of existing cells by programmed cell death. Cells compete for growth and survival factors to ensure an appropriate balance between the addition and elimination of cells. Elaborate mechanisms ensure that cells do not evade these constraints, and thereby prevent uncontrolled proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Myc regulation of G1–S progression.
Figure 2: Simplified model of intrinsic and extrinsic apoptosis pathways.
Figure 3: The ARF–MDM2–p53 response to activated oncogenes.
Figure 4: Slik-driven growth is opposed by apoptosis.
Figure 5: The Hippo–Salvador–Warts complex suppresses tissue growth.
Figure 6: Involvement of the Hippo–Salvador–Warts complex in apoptosis and proliferation.

Similar content being viewed by others

References

  1. Edgar, B. A. & Orr-Weaver, T. L. Endoreplication cell cycles: more for less. Cell 105, 297–306 (2001).

    CAS  PubMed  Google Scholar 

  2. Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975).

    CAS  PubMed  Google Scholar 

  3. Grandori, C., Cowley, S. M., James, L. P. & Eisenman, R. N. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 16, 653–699 (2000).

    CAS  PubMed  Google Scholar 

  4. Pelengaris, S., Khan, M. & Evan, G. c-MYC: more than just a matter of life and death. Nature Rev. Cancer 2, 764–776 (2002).

    CAS  Google Scholar 

  5. Eisenman, R. N. Deconstructing myc. Genes Dev. 15, 2023–2030 (2001).

    CAS  PubMed  Google Scholar 

  6. Levens, D. Disentangling the MYC web. Proc. Natl Acad. Sci. USA 9, 5757–5759 (2002).

    Google Scholar 

  7. Fernandez, P. C. et al. Genomic targets of the human c-Myc protein. Genes Dev. 17, 1115–1129 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Orian, A. et al. Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 17, 1101–1114 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zeller, K. I., Jegga, A. G., Aronow, B. J., O'Donnell, K. A. & Dang, C. V. An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol. 4, R69 (2003).

    PubMed  PubMed Central  Google Scholar 

  10. Bouchard, C. et al. Regulation of cyclin D2 gene expression by the Myc/Max/Mad network: Myc-dependent TRRAP recruitment and histone acetylation at the cyclin D2 promoter. Genes Dev. 15, 2042–2047 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hermeking, H. et al. Identification of CDK4 as a target of c-MYC. Proc. Natl Acad. Sci. USA 97, 2229–2234 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Perez-Roger, I., Solomon, D. L., Sewing, A. & Land, H. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27Kip1 binding to newly formed complexes. Oncogene 14, 2373–2381 (1997).

    CAS  PubMed  Google Scholar 

  13. O'Connell, B. C. et al. A large scale genetic analysis of c-Myc-regulated gene expression patterns. J. Biol. Chem. 278, 12563–12573 (2003).

    CAS  PubMed  Google Scholar 

  14. Sears, R., Ohtani, K. & Nevins, J. R. Identification of positively and negatively acting elements regulating expression of the E2F2 gene in response to cell growth signals. Mol. Cell. Biol. 17, 5227–5235 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 (1999). First papers (see also reference 30) implicating the Myc oncogene in the control of cellular growth and size in animal development.

    CAS  PubMed  Google Scholar 

  16. Prober, D. A. & Edgar, B. A. Ras1 promotes cellular growth in the Drosophila wing. Cell 100, 435–446 (2000).

    CAS  PubMed  Google Scholar 

  17. Neufeld, T. P., de la Cruz, A. F., Johnston, L. A. & Edgar, B. A. Coordination of growth and cell division in the Drosophila wing. Cell 93, 1183–1193 (1998). Shows that, as in yeast, cell division and cellular growth are separable processes in higher eukaryotes, and that tissue size is not measured in terms of the number of cell divisions, but in terms of mass.

    Article  CAS  PubMed  Google Scholar 

  18. Geng, Y. et al. Cyclin E ablation in the mouse. Cell 114, 431–443 (2003).

    CAS  PubMed  Google Scholar 

  19. Claassen, G. F. & Hann, S. R. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest. Proc. Natl Acad. Sci. USA 97, 9498–9503 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Coller, H. A. et al. Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc. Natl Acad. Sci. USA 97, 3260–3265 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang, W. et al. Repression of transcription of the p27Kip1 cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 20, 1688–1702 (2001).

    CAS  PubMed  Google Scholar 

  22. Staller, P. et al. Repression of p15INK4b expression by Myc through association with Miz-1. Nature Cell Biol. 3, 392–399 (2001).

    CAS  PubMed  Google Scholar 

  23. Martins, C. P. & Berns, A. Loss of p27Kip1 but not p21Cip1 decreases survival and synergizes with MYC in murine lymphomagenesis. EMBO J. 21, 3739–3748 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Fero, M. L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice. Cell 85, 733–744 (1996).

    CAS  PubMed  Google Scholar 

  25. Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27Kip1. Cell 85, 721–732 (1996).

    CAS  PubMed  Google Scholar 

  26. Nakayama, K. et al. Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996).

    CAS  PubMed  Google Scholar 

  27. Schmid, P., Schulz, W. A. & Hameister, H. Dynamic expression pattern of the myc protooncogene in midgestation mouse embryos. Science 243, 226–229 (1989).

    CAS  PubMed  Google Scholar 

  28. Davis, A. C., Wims, M., Spotts, G. D., Hann, S. R. & Bradley, A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 7, 671–682 (1993).

    CAS  PubMed  Google Scholar 

  29. Trumpp, A. et al. c-Myc regulates mammalian body size by controlling cell number but not cell size. Nature 414, 768–773 (2001). Shows that mammalian c-MYC controls organ and body size by regulating cell numbers.

    CAS  PubMed  Google Scholar 

  30. Gallant, P., Shiio, Y., Cheng, P. F., Parkhurst, S. M. & Eisenman, R. N. Myc and Max homologs in Drosophila. Science 274, 1523–1527 (1996).

    CAS  PubMed  Google Scholar 

  31. Bourbon, H. M. et al. A P-insertion screen identifying novel X-linked essential genes in Drosophila. Mech. Dev. 110, 71–83 (2002).

    CAS  PubMed  Google Scholar 

  32. de la Cova, C., Abrili, M., Bellosta, P., Gallant, P. & Johnston, L. A. Drosophila Myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004). Together with references 114 and 122, provides strong evidence that cell competition contributes significantly to the control of organ size.

    CAS  PubMed  Google Scholar 

  33. Mateyak, M. K., Obaya, A. J., Adachi, S. & Sedivy, J. M. Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ. 8, 1039–1048 (1997).

    CAS  PubMed  Google Scholar 

  34. Thomas, G. An encore for ribosome biogenesis in the control of cell proliferation. Nature Cell Biol. 2, E71–E72 (2000).

    CAS  PubMed  Google Scholar 

  35. Conlon, I. & Raff, M. Differences in the way a mammalian cell and yeast cells coordinate cell growth and cell-cycle progression. J. Biol. 2, 7 (2003).

    PubMed  PubMed Central  Google Scholar 

  36. Lambertsson, A. The minute genes in Drosophila and their molecular functions. Adv. Genet. 38, 69–134 (1998).

    CAS  PubMed  Google Scholar 

  37. Saucedo, L. J. & Edgar, B. A. Why size matters: altering cell size. Curr. Opin. Genet. Dev. 12, 565–571 (2002).

    CAS  PubMed  Google Scholar 

  38. Reis, T. & Edgar, B. A. Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing. Cell 117, 253–264 (2004).

    CAS  PubMed  Google Scholar 

  39. Askew, D. S., Ashmun, R. A., Simmons, B. C. & Cleveland, J. L. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 6, 1915–1922 (1991).

    CAS  PubMed  Google Scholar 

  40. Evan, G. I. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69, 119–128 (1992). References 39 and 40 report the striking finding that an oncogene induces apoptosis.

    CAS  PubMed  Google Scholar 

  41. Harrington, E. A., Bennett, M. R., Fanidi, A. & Evan, G. I. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 13, 3286–3295 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Pelengaris, S., Khan, M. & Evan, G. I. Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002). Shows that complex angiogenic and invasive tumours can be generated by driving proliferation and blocking apoptosis, without the need for additional mutations.

    CAS  PubMed  Google Scholar 

  43. Nilsson, J. A. & Cleveland, J. L. Myc pathways provoking cell suicide and cancer. Oncogene 22, 9007–9021 (2003).

    CAS  PubMed  Google Scholar 

  44. Juin, P., Hueber, A. O., Littlewood, T. & Evan, G. c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release. Genes Dev. 13, 1367–1381 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Maclean, K. H., Keller, U. B., Rodriguez-Galindo, C., Nilsson, J. A. & Cleveland, J. L. c-Myc augments γ irradiation-induced apoptosis by suppressing Bcl-XL . Mol. Cell. Biol. 23, 7256–7270 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Iaccarino, I., Hancock, D., Evan, G. & Downward, J. c-Myc induces cytochrome c release in Rat1 fibroblasts by increasing outer mitochondrial membrane permeability in a Bid-dependent manner. Cell Death Differ. 10, 599–608 (2003).

    CAS  PubMed  Google Scholar 

  47. Eischen, C. M., Woo, D., Roussel, M. F. & Cleveland, J. L. Apoptosis triggered by Myc-induced suppression of Bcl-XL or Bcl-2 is bypassed during lymphomagenesis. Mol. Cell. Biol. 21, 5063–5070 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Eischen, C. M. et al. Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1. Oncogene 20, 6983–6993 (2001).

    CAS  PubMed  Google Scholar 

  49. Mitchell, K. O. et al. Bax is a transcriptional target and mediator of c-myc-induced apoptosis. Cancer Res. 60, 6318–6325 (2000).

    CAS  PubMed  Google Scholar 

  50. Juin, P. et al. c-Myc functionally cooperates with Bax to induce apoptosis. Mol. Cell. Biol. 22, 6158–6169 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Morrish, F., Giedt, C. & Hockenbery, D. c-MYC apoptotic function is mediated by NRF-1 target genes. Genes Dev. 17, 240–255 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Hueber, A. O. et al. Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. Science 278, 1305–1309 (1997).

    CAS  PubMed  Google Scholar 

  53. Amanullah, A., Liebermann, D. A. & Hoffman, B. Deregulated c-Myc prematurely recruits both Type I and II CD95/Fas apoptotic pathways associated with terminal myeloid differentiation. Oncogene 21, 1600–1610 (2002).

    CAS  PubMed  Google Scholar 

  54. Klefstrom, J., Verschuren, E. W. & Evan, G. c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway. J. Biol. Chem. 277, 43224–43232 (2002).

    CAS  PubMed  Google Scholar 

  55. Vafa, O. et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol. Cell 9, 1031–1044 (2002).

    CAS  PubMed  Google Scholar 

  56. Tanaka, H. et al. E2F1 and c-Myc potentiate apoptosis through inhibition of NF-κB activity that facilitates MnSOD-mediated ROS elimination. Mol. Cell 9, 1017–1029 (2002).

    CAS  PubMed  Google Scholar 

  57. Green, D. R. & Evan, G. I. A matter of life and death. Cancer Cell 1, 19–30 (2002).

    CAS  PubMed  Google Scholar 

  58. Evan, G. & Littlewood, T. A matter of life and cell death. Science 281, 1317–1322 (1998).

    CAS  PubMed  Google Scholar 

  59. Schmitt, C. A., McCurrach, M. E., de Stanchina, E., Wallace-Brodeur, R. R. & Lowe, S. W. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev. 13, 2670–2677 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678–2690 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Strasser, A., Harris, A. W., Bath, M. L. & Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331–333 (1990).

    CAS  PubMed  Google Scholar 

  62. Eischen, C. M., Roussel, M. F., Korsmeyer, S. J. & Cleveland, J. L. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol. Cell. Biol. 21, 7653–7662 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Blyth, K. et al. Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss. Oncogene 10, 1717–1723 (1995).

    CAS  PubMed  Google Scholar 

  64. Elson, A., Deng, C., Campos-Torres, J., Donehower, L. A. & Leder, P. The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice. Oncogene 11, 181–190 (1995).

    CAS  PubMed  Google Scholar 

  65. Russell, J. L. et al. ARF differentially modulates apoptosis induced by E2F1 and Myc. Mol. Cell. Biol. 22, 1360–1368 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Eischen, C. M., Weber, J. D., Roussel, M. F., Sherr, C. J. & Cleveland, J. L. Disruption of the ARF–Mdm2–p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13, 2658–2669 (1999). Shows that induction of tumours by Myc in vivo selects for disruption of ARF–MDM2–p53 regulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Fridman, J. S. et al. Tumor promotion by Mdm2 splice variants unable to bind p53. Cancer Res. 63, 5703–5706 (2003).

    CAS  PubMed  Google Scholar 

  68. Alt, J. R., Greiner, T. C., Cleveland, J. L. & Eischen, C. M. Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J. 22, 1442–1450 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zindy, F. et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12, 2424–2433 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zindy, F. et al. Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc. Natl Acad. Sci. USA 100, 15930–15935 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).

    CAS  PubMed  Google Scholar 

  72. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).

    CAS  PubMed  Google Scholar 

  73. Sogame, N., Kim, M. & Abrams, J. M. Drosophila p53 preserves genomic stability by regulating cell death. Proc. Natl Acad. Sci. USA 100, 4696–4701 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998).

    CAS  PubMed  Google Scholar 

  75. Pinto, D., Gregorieff, A., Begthel, H. & Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, 1709–1713 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. van de Wetering, M. et al. The α-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).

    CAS  PubMed  Google Scholar 

  77. He, T. C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998).

    CAS  PubMed  Google Scholar 

  78. You, Z. et al. Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J. Cell Biol. 157, 429–440 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Altieri, D. C. Validating survivin as a cancer therapeutic target. Nature Rev. Cancer 3, 46–54 (2003).

    CAS  Google Scholar 

  80. Zhang, T. et al. Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res. 61, 8664–8667 (2001).

    CAS  PubMed  Google Scholar 

  81. Kim, P. J., Plescia, J., Clevers, H., Fearon, E. R. & Altieri, D. C. Survivin and molecular pathogenesis of colorectal cancer. Lancet 362, 205–209 (2003).

    CAS  PubMed  Google Scholar 

  82. Hipfner, D. R. & Cohen, S. M. The Drosophila Sterile-20 kinase Slik controls cell proliferation and apoptosis during imaginal disc development. PLoS Biol. 1, 244–256 (2003).

    CAS  Google Scholar 

  83. Wu, S., Huang, J., Dong, J. & Pan, D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445–456 (2003).

    CAS  PubMed  Google Scholar 

  84. Udan, R. S., Kango-Singh, M., Nolo, R., Tao, C. & Halder, G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature Cell Biol. 5, 914–920 (2003).

    CAS  PubMed  Google Scholar 

  85. Pantalacci, S., Tapon, N. & Leopold, P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nature Cell Biol. 5, 921–927 (2003).

    CAS  PubMed  Google Scholar 

  86. Harvey, K. F., Pfleger, C. M. & Hariharan, I. K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457–467 (2003). References 83–86 clearly show the close coordination of apoptosis and proliferation control in vivo through the characterization of a tumour-suppressor protein complex in flies that might be relevant to cancer.

    CAS  PubMed  Google Scholar 

  87. Hipfner, D. R., Weigmann, K. & Cohen, S. M. The bantam gene regulates Drosophila growth. Genetics 161, 1527–1537 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B. & Cohen, S. M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003). Characterization of the first microRNA that controls growth and apoptosis.

    CAS  PubMed  Google Scholar 

  89. Du, W., Xie, J. E. & Dyson, N. Ectopic expression of dE2F and dDP induces cell proliferation and death in the Drosophila eye. EMBO J. 15, 3684–3692 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Prober, D. A. & Edgar, B. A. Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing. Genes Dev. 16, 2286–2299 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Sears, R., Leone, G., DeGregori, J. & Nevins, J. R. Ras enhances Myc protein stability. Mol. Cell 3, 169–179 (1999).

    CAS  PubMed  Google Scholar 

  92. Bergmann, A., Agapite, J., McCall, K. & Steller, H. The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling. Cell 95, 331–341 (1998).

    CAS  PubMed  Google Scholar 

  93. Kurada, P. & White, K. Ras promotes cell survival in Drosophila by downregulating hid expression. Cell 95, 319–329 (1998).

    CAS  PubMed  Google Scholar 

  94. Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G. & Cheresh, D. A. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301, 94–96 (2003).

    CAS  PubMed  Google Scholar 

  95. Hindley, A. & Kolch, W. Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases. J. Cell Sci. 115, 1575–1581 (2002).

    CAS  PubMed  Google Scholar 

  96. Huser, M. et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 20, 1940–1951 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Yang, L. & Baker, N. E. Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye. Dev. Cell 4, 359–369 (2003).

    CAS  PubMed  Google Scholar 

  98. Raisin, S., Pantalacci, S., Breittmayer, J. P. & Leopold, P. A new genetic locus controlling growth and proliferation in Drosophila melanogaster. Genetics 164, 1015–1025 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Johnston, L. A. & Gallant, P. Control of growth and organ size in Drosophila. Bioessays 24, 54–64 (2002).

    CAS  PubMed  Google Scholar 

  100. Oldham, S. & Hafen, E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol. 13, 79–85 (2003).

    CAS  PubMed  Google Scholar 

  101. Datar, S. A., Jacobs, H. W., de la Cruz, A. F., Lehner, C. F. & Edgar, B. A. The Drosophila cyclin D–Cdk4 complex promotes cellular growth. EMBO J. 19, 4543–4554 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Meyer, C. A. et al. Drosophila Cdk4 is required for normal growth and is dispensable for cell cycle progression. EMBO J. 19, 4533–4542 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Frei, C. & Edgar, B. A. Drosophila cyclin D/Cdk4 requires hif-1 prolyl hydroxylase to drive cell growth. Dev. Cell 6, 241–251 (2004).

    CAS  PubMed  Google Scholar 

  104. Justice, R. W., Zilian, O., Woods, D. F., Noll, M. & Bryant, P. J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534–546 (1995).

    CAS  PubMed  Google Scholar 

  105. Kango-Singh, M. et al. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719–5730 (2002).

    CAS  PubMed  Google Scholar 

  106. Tapon, N. et al. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467–478 (2002).

    CAS  PubMed  Google Scholar 

  107. Xu, T., Wang, W., Zhang, S., Stewart, R. A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053–1063 (1995).

    CAS  PubMed  Google Scholar 

  108. Tamaskovic, R., Bichsel, S. J. & Hemmings, B. A. NDR family of AGC kinases — essential regulators of the cell cycle and morphogenesis. FEBS Lett. 546, 73–80 (2003).

    CAS  PubMed  Google Scholar 

  109. Dan, I., Watanabe, N. M. & Kusumi, A. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol. 11, 220–230 (2001).

    CAS  PubMed  Google Scholar 

  110. Stewart, R. A., Li, D. M., Huang, H. & Xu, T. A genetic screen for modifiers of the lats tumor suppressor gene identifies C-terminal Src kinase as a regulator of cell proliferation in Drosophila. Oncogene 22, 6436–6444 (2003).

    CAS  PubMed  Google Scholar 

  111. Cheung, W. L. et al. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113, 507–517 (2003).

    CAS  PubMed  Google Scholar 

  112. Conlon, I. & Raff, M. Size control in animal development. Cell 96, 235–244 (1999).

    CAS  PubMed  Google Scholar 

  113. Simpson, P. & Morata, G. Differential mitotic rates and patterns of growth in compartments in the Drosophila wing. Dev. Biol. 85, 299–308 (1981). Provides evidence that faster-dividing cells out compete those that divide more slowly in developing tissues. Sets the stage for much of the recent progress in understanding size control.

    CAS  PubMed  Google Scholar 

  114. Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell 117, 117–129 (2004).

    CAS  PubMed  Google Scholar 

  115. Burke, R. & Basler, K. Dpp receptors are autonomously required for cell proliferation in the entire developing Drosophila wing. Development 122, 2261–2269 (1996).

    CAS  PubMed  Google Scholar 

  116. Martin-Castellanos, C. & Edgar, B. A. A characterization of the effects of Dpp signaling on cell growth and proliferation in the Drosophila wing. Development 129, 1003–1013 (2002).

    CAS  PubMed  Google Scholar 

  117. Johnston, L. A. & Sanders, A. L. Wingless promotes cell survival but constrains growth during Drosophila wing development. Nature Cell Biol. 5, 827–833 (2003).

    CAS  PubMed  Google Scholar 

  118. Giraldez, A. J. & Cohen, S. M. Wingless and Notch signaling provide cell survival cues and control cell proliferation during wing development. Development 130, 6533–6543 (2003).

    CAS  PubMed  Google Scholar 

  119. Nellen, D., Burke, R., Struhl, G. & Basler, K. Direct and long-range action of a DPP morphogen gradient. Cell 85, 357–368 (1996).

    CAS  PubMed  Google Scholar 

  120. Lecuit, T. et al. Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila. Nature 381, 387–393 (1996).

    CAS  PubMed  Google Scholar 

  121. Adachi-Yamada, T., Fujimura-Kamada, K., Nishida, Y. & Matsumoto, K. Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature 400, 166–169 (1999).

    CAS  PubMed  Google Scholar 

  122. Moreno, E., Basler, K. & Morata, G. Cells compete for decapentaplegic survival factor to prevent apoptosis in Drosophila wing development. Nature 416, 755–759 (2002). References 114 and 122 provide evidence that cells might compete for limiting levels of a survival ligand in vivo.

    CAS  PubMed  Google Scholar 

  123. Duman-Scheel, M., Weng, L., Xin, S. & Du, W. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 417, 299–304 (2002).

    CAS  PubMed  Google Scholar 

  124. Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E. & Waterfield, M. D. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 15, 6584–6594 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Milan, M., Campuzano, S. & Garcia-Bellido, A. Developmental parameters of cell death in the wing disc of Drosophila. Proc. Natl Acad. Sci. USA 94, 5691–5696 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Tao, W. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nature Genet. 21, 177–181 (1999).

    CAS  PubMed  Google Scholar 

  127. St John, M. A. et al. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nature Genet. 21, 182–186 (1999).

    CAS  PubMed  Google Scholar 

  128. Hisaoka, M., Tanaka, A. & Hashimoto, H. Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest. 82, 1427–1435 (2002).

    CAS  PubMed  Google Scholar 

  129. Sibilia, M. et al. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell 102, 211–220 (2000).

    CAS  PubMed  Google Scholar 

  130. Li, Y., Hively, W. P. & Varmus, H. E. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 19, 1002–1009 (2000).

    CAS  PubMed  Google Scholar 

  131. Oro, A. E. et al. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276, 817–821 (1997).

    CAS  PubMed  Google Scholar 

  132. Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001).

    CAS  PubMed  Google Scholar 

  133. Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Berman, D. M. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003).

    CAS  PubMed  Google Scholar 

  135. Sun, X., Mariani, F. V. & Martin, G. R. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418, 501–508 (2002).

    CAS  PubMed  Google Scholar 

  136. Megason, S. G. & McMahon, A. P. A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. Development 129, 2087–2098 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank L. Johnston for kindly sharing results before publication, and J. Brennecke, S. Pizette, S. Szuplewski, D. Neubueser and M. Treier for discussions, comments and suggestions.

Author information

Authors and Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, 169117, Germany

    David R. Hipfner & Stephen M. Cohen

Authors
  1. David R. Hipfner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen M. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

ARF

MDM2

Myc

slik

Flybase

bantam

brinker

Hid

Hippo

salvador

Slik

warts

Wingless

SwissProt

c-Myc

L-Myc

N-Myc

p53

PUMA

Glossary

CELL GROWTH

An increase in cell mass.

ONCOGENE

A gene that is causally linked to the formation of tumours in vivo, usually as a result of mutant forms of the gene.

BASIC HELIX–LOOP–HELIX LEUCINE-ZIPPER PROTEIN

A type of transcription factor with a basic domain, a 'helix–loop–helix' DNA-binding motif and a 'leucine zipper' dimerization domain.

CYCLINS

A family of proteins, the levels of which fluctuate throughout the cell cycle. By activating cyclin-dependent kinases, they regulate the cell cycle. D- and E-type cyclins promote G1–S phase progression; A- and B-type cyclins regulate S–G2–M progression.

E2F PROTEINS

Members of a family of transcription factors that control the expression of genes that are involved in cell-cycle progression, including cyclin E, string CDC25 phosphatase and components of the DNA-synthesis machinery.

WING IMAGINAL DISCS

Imaginal discs are the larval precursors of adult structures. The wing imaginal discs make the dorsal thorax and the wing appendages.

HYPOMORPHIC

A mutation that reduces, but does not completely eliminate, the function of a gene.

PRIMARY CELLS

Cultured cells that are derived directly from tissue (often embryonic tissue). They are distinct from transformed cell lines.

CELL-SIZE CHECKPOINT

A mechanism that ensures that cells divide at a defined size.

MINUTE MUTATIONS

A class of mutations that produce a dominant growth defect. Minutes are caused by the mutation of genes that encode any of several ribosomal proteins.

BH3-ONLY DOMAIN PROTEINS

Members of a class of pro-apoptotic proteins in the larger BCL2 family that contain a single 'BCL2 homology-3' domain.

EXTRINSIC DEATH PATHWAY

An apoptotic signalling pathway that is activated by binding of secreted ligands to 'death receptors' of the tumour-necrosis-factor-receptor family.

MITOGENIC

Promotes cell proliferation.

INTRINSIC DEATH PATHWAY

An apoptotic signalling pathway that is activated in response to various forms of intracellular stress.

BCL2

An anti-apoptotic protein. It is the founding member of the BCL2 family of pro- and anti-apoptotic proteins.

E3 UBIQUITIN PROTEIN LIGASE

An enzyme that catalyses the addition of ubiquitin to target proteins, which signals their degradation via the proteasome pathway.

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis.

STERILE 20 KINASE

A member of a diverse family of serine/threonine protein kinases that share homology with the yeast Ste20 kinase.

microRNA

A small RNA of ∼22 nucleotides that is encoded by an endogenous gene. The microRNA regulates expression of RNAs to which it is complementary in sequence.

ORTHOLOGUE

Functionally related genes with extensive sequence similarity, which indicates a common ancestor. Orthologues are often used to indicate the most closely related members of larger gene families in different species.

WW DOMAIN

A protein domain that is involved in binding to proline-rich peptide motifs.

SCAFFOLD

A protein that functions as a support to assemble a multiprotein complex.

CELL COMPETITION

A phenomenon that is observed in imaginal discs — slowly dividing cells are eliminated by apoptosis owing to competition with faster-dividing cells.

GENETIC MOSAICS

Tissues that are composed of cells of different genotypes. They are usually generated by controlled recombination during mitosis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hipfner, D., Cohen, S. Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol 5, 805–815 (2004). https://doi.org/10.1038/nrm1491

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1491

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing