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Growth-factor-dependent mitogenesis requires two distinct phases of signalling

Nature Cell Biology volume 3, pages 165–172 (2001)Cite this article

Abstract

Prolonged and continuous exposure to growth factors is required to commit cells to the cell cycle. Here we show that the prolonged requirement for growth factor can be replaced with two short pulses of mitogen. The first pulse of growth factor moves the cell through the initial segment of the G0 to S interval. This initial pulse also makes cells responsive to a second pulse of growth factor, which engages components of the cell-cycle machinery necessary for progression into S phase. We also show that activation of MAP kinase kinase (MEK) and induction of the transcription factor c-Myc are sufficient to drive the first, but not the second, phase of signalling. Furthermore, synthetic phosphatidylinositol-3-OH kinase (PI(3)K) lipid products are sufficient to drive the second phase of signalling, but not the first. These findings suggest that there is a common signalling cascade by which mitogens drive arrested cells into the cell cycle, and that this cascade involves the temporally coordinated input of MEK, c-Myc and PI(3)K.

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Figure 1: G0 cells can be driven into S phase by either continuous or discontinuous treatment with PDGF.
Figure 2: Discontinuous stimulation with PDGF drives the cell-cycle machinery and progression through the cell cycle.
Figure 3: c-Myc and MEK are sufficient to drive the initial phase of signalling.
Figure 4: Growth factors differ in their ability to drive the initial phase of signalling.
Figure 5: PI(3)K lipid products can substitute for PDGF during the second, but not the first phase of the discontinuous treatment assays.
Figure 6: Model of growth factor events of the early cell cycle.

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Acknowledgements

We would like to thank M. Roussel for both the NIH3T3 cells expressing inducible MEK1* and the c-Myc retrovirus. We also appreciate the critical input of C. Sherr, M. Roussel, J. Pledger, C. Stiles, T. Langan, E. Balciunaite, M. Nickas and Y. Ikuno. This work was supported by an NIH grant (to A.K.) and an NIH postdoctoral fellowship (to S.M.J).

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Authors and Affiliations

  1. Schepens Eye Research Institute, 20 Staniford Street, Boston, 02114, Massachusetts, USA

    Steven M. Jones & Andrius Kazlauskas

  2. Department of Ophthalmology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Steven M. Jones & Andrius Kazlauskas

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  1. Steven M. Jones
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  2. Andrius Kazlauskas
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Correspondence to Andrius Kazlauskas.

Supplementary information

Figure 1 Continuous exposure to PDGF for less than 10 h compromises the mitogenic response.

Figure 2 MEK activity is necessary for the initial phase of signalling. (PDF 122 kb)

Figure 3 Expression of c-Myc to physiological levels does not deregulate growth factor-dependence for cell-cycle progression.

Figure 4 A 30-min pulse of PDGF is required to fully activate Erk and elevate c-Myc.

Figure 5 The second phase of signalling is transient and can be driven by synthetic PI(3)K lipid products.

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Jones, S., Kazlauskas, A. Growth-factor-dependent mitogenesis requires two distinct phases of signalling . Nat Cell Biol 3, 165–172 (2001). https://doi.org/10.1038/35055073

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