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Growth factor modulation of p53-mediated growth arrest versus apoptosis.

Publication ,  Journal Article
Canman, CE; Gilmer, TM; Coutts, SB; Kastan, MB
Published in: Genes Dev
March 1, 1995

Irradiation of mammalian cells can cause cell cycle perturbations and apoptotic cell death. We have investigated the modulation of these physiologic end points by growth factor stimulation: irradiation of a murine hematopoietic cell line in the presence of interlekin-3 (IL-3) induces G1 arrest, and irradiation in the absence of IL-3 results in rapid apoptotic cell death. Both of these end points are dependent on p53. Transient removal of IL-3 at the time of irradiation results in decreased clonogenic survival of irradiated cells. The removal of IL-3 results in a failure of the irradiated cells to arrest at the G1 checkpoint, despite induction of p53 and p21WAF1/CIP1, and then the cells enter S-phase where they undergo apoptosis. There are no cytokine-related changes in Bcl-2, Bax, or Bcl-x protein levels that could account for the modulation of G1 arrest versus apoptosis by growth factors. In contrast, rapid p53-independent alterations of basal levels of gadd45 and p21WAF1/CIP1 expression are linked to IL-3 withdrawal, suggesting a potential mechanism for this modulation. Constitutive activation of cytokine-like pathways with induced expression of v-Src or activated c-Raf inhibits the radiation-induced apoptosis and the alterations in p21WAF1/CIP1 and gadd45 expression. These observations suggest additional molecular mechanisms that can contribute to the development of radioresistance and resistance to apoptosis during tumorigenesis and provide an explanation for the observed lack of p53 mutations in some tumor types. In addition, these data suggest that oncogenic changes occurring during multistep tumorigenesis could be classified as those that either enhance or decrease apoptosis tendencies.

Duke Scholars

Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

March 1, 1995

Volume

9

Issue

5

Start / End Page

600 / 611

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Repressor Proteins
  • RNA, Messenger
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins
  • Proteins
  • Oncogene Proteins, Viral
  • Oncogene Protein pp60(v-src)
  • Nuclear Proteins
  • Mice
 

Citation

APA
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ICMJE
MLA
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Canman, C. E., Gilmer, T. M., Coutts, S. B., & Kastan, M. B. (1995). Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev, 9(5), 600–611. https://doi.org/10.1101/gad.9.5.600
Canman, C. E., T. M. Gilmer, S. B. Coutts, and M. B. Kastan. “Growth factor modulation of p53-mediated growth arrest versus apoptosis.Genes Dev 9, no. 5 (March 1, 1995): 600–611. https://doi.org/10.1101/gad.9.5.600.
Canman CE, Gilmer TM, Coutts SB, Kastan MB. Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev. 1995 Mar 1;9(5):600–11.
Canman, C. E., et al. “Growth factor modulation of p53-mediated growth arrest versus apoptosis.Genes Dev, vol. 9, no. 5, Mar. 1995, pp. 600–11. Pubmed, doi:10.1101/gad.9.5.600.
Canman CE, Gilmer TM, Coutts SB, Kastan MB. Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev. 1995 Mar 1;9(5):600–611.

Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

March 1, 1995

Volume

9

Issue

5

Start / End Page

600 / 611

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Repressor Proteins
  • RNA, Messenger
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins
  • Proteins
  • Oncogene Proteins, Viral
  • Oncogene Protein pp60(v-src)
  • Nuclear Proteins
  • Mice