Regulation of p53 stabilization by DNA damage and protein kinase C

Cassie L. Johnson, Dongmei Lu, Jie Huang, Alakananda Basu

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We have demonstrated previously that the protein kinase C (PKC) signal transduction pathway acts upstream of caspases to regulate caspase activation and apoptosis induced by the DNA-damaging agent cisplatin (CP). In the present study, we have examined whether PKC influences p53 and, hence, cellular sensitivity/resistance to CP. The basal p53 level was low in HeLa cells but was elevated in CP-resistant HeLa (HeLa/CP) cells. CP had no effect on the p53 content in HeLa cells, but it caused p53 accumulation in HeLa/CP cells. Rottlerin, a PKCδ inhibitor that prevents CP-induced proteolytic activation of PKCδ, caused an accumulation of p53 in HeLa cells when treated in conjunction with CP, but it had no additional effect in HeLa/CP cells. The ability of rottlerin to prevent proteolytic activation of PKCδ or to induce accumulation of p53 by CP was compromised in HeLa/CP cells. PKC activator phorbol 12, 13-dibutyrate attenuated constitutive p53 levels in both HeLa and HeLa/CP cells. Whereas the combination of rottlerin and CP increased the half-life of p53 in HeLa cells, CP alone was sufficient to stabilize p53 in HeLa/CP cells. These results suggest that both DNA damage and inhibition of proteolytic activation of PKCδ by CP were necessary for the stabilization of p53 in HeLa cells. Furthermore, an increase in p53 was not associated with enhanced sensitivity of HeLa cells to CP.

Original languageEnglish
Pages (from-to)861-867
Number of pages7
JournalMolecular Cancer Therapeutics
Volume1
Issue number10
StatePublished - 1 Aug 2002

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Polynucleotide 5'-Hydroxyl-Kinase
Protein Kinase C
Cisplatin
DNA Damage
HeLa Cells
Caspases
Phorbol 12,13-Dibutyrate

Cite this

Johnson, Cassie L. ; Lu, Dongmei ; Huang, Jie ; Basu, Alakananda. / Regulation of p53 stabilization by DNA damage and protein kinase C. In: Molecular Cancer Therapeutics. 2002 ; Vol. 1, No. 10. pp. 861-867.
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Regulation of p53 stabilization by DNA damage and protein kinase C. / Johnson, Cassie L.; Lu, Dongmei; Huang, Jie; Basu, Alakananda.

In: Molecular Cancer Therapeutics, Vol. 1, No. 10, 01.08.2002, p. 861-867.

Research output: Contribution to journalArticle

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