IGF1 activates cell cycle arrest following irradiation by reducing binding of ΔNp63 to the p21 promoter

G. C. Mitchell, J. L. Fillinger, S. Sittadjody, J. L. Avila, Randy M Burd, Kirsten Limesand

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Radiotherapy for head and neck tumors often results in persistent loss of function in salivary glands. Patients suffering from impaired salivary function frequently terminate treatment prematurely because of reduced quality of life caused by malnutrition and other debilitating side-effects. It has been previously shown in mice expressing a constitutively active form of Akt (myr-Akt1), or in mice pretreated with IGF1, apoptosis is suppressed, which correlates with maintained salivary gland function measured by stimulated salivary flow. Induction of cell cycle arrest may be important for this protection by allowing cells time for DNA repair. We have observed increased accumulation of cells in G2/M at acute time-points after irradiation in parotid glands of mice receiving pretreatment with IGF1. As p21, a transcriptional target of the p53 family, is necessary for maintaining G2/M arrest, we analyzed the roles of p53 and p63 in modulating IGF1-stimulated p21 expression. Pretreatment with IGF1 reduces binding of DNp63 to the p21 promoter after irradiation, which coincides with increased p53 binding and sustained p21 transcription. Our data indicate a role for ΔNp63 in modulating p53-dependent gene expression and influencing whether a cell death or cell cycle arrest program is initiated.

Original languageEnglish (US)
Article numbere50
JournalCell Death and Disease
Volume1
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Cell Cycle Checkpoints
Salivary Glands
Cytoprotection
Parotid Gland
p53 Genes
Malnutrition
DNA Repair
Cell Death
Neck
Radiotherapy
Head
Quality of Life
Apoptosis
Gene Expression
Neoplasms
Therapeutics

Keywords

  • Cell cycle arrest
  • IGF1
  • P53
  • P63
  • Radiation
  • Xerostomia

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

IGF1 activates cell cycle arrest following irradiation by reducing binding of ΔNp63 to the p21 promoter. / Mitchell, G. C.; Fillinger, J. L.; Sittadjody, S.; Avila, J. L.; Burd, Randy M; Limesand, Kirsten.

In: Cell Death and Disease, Vol. 1, No. 6, e50, 06.2010.

Research output: Contribution to journalArticle

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