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Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells.

ABSTRACT: The cyclin-dependent kinase inhibitor p21(Cip1) plays an important role in the cellular response to DNA damage. In normal cells, genotoxic stress activates the ATM-p53 pathway that up-regulates the expression of p21(Cip1) leading to cell cycle arrest. However, we have found that in several neoplastic cell lines, ionizing radiation (IR) induces ubiquitin-dependent degradation of p21(Cip1). This process is independent of the ATM pathway as it occurs in immortalized A-T fibroblasts. Knockdown of Skp2, an F-box protein capable of regulating the normal turnover of p21(Cip1), does not prevent the IR-induced degradation. Instead, this process requires the Cul4-DDB1(Cdt2) E3 ligase as knockdown of either DDB1 or Cdt2 rescues p21(Cip1) degradation after IR. Mutating the proliferating cell nuclear antigen-binding site of p21(Cip1) also prevents its IR-induced degradation suggesting that the p21(Cip1)-proliferating cell nuclear antigen interaction is critical for this event. Although ectopic expression of a nondegradable p21(Cip1) did not by itself affect the clonogenic survival of HEK293 cells after IR, the degradation of p21(Cip1) and other targets of the Cul4-DDB1(Cdt2) E3 ligase may collectively contribute to the survival of neoplastic cells after ionizing radiation.

SUBMITTER: Stuart SA

PROVIDER: S-EPMC2685688 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells.

Stuart Scott A SA Wang Jean Y J JY

The Journal of biological chemistry 20090330 22

The cyclin-dependent kinase inhibitor p21(Cip1) plays an important role in the cellular response to DNA damage. In normal cells, genotoxic stress activates the ATM-p53 pathway that up-regulates the expression of p21(Cip1) leading to cell cycle arrest. However, we have found that in several neoplastic cell lines, ionizing radiation (IR) induces ubiquitin-dependent degradation of p21(Cip1). This process is independent of the ATM pathway as it occurs in immortalized A-T fibroblasts. Knockdown of Sk ...[more]

PMID: 19332548

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Project description:BackgroundIonizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times also lead to stress responses, which counteract IR-induced cytotoxicity. IR also triggers cellular secretion of vascular endothelial growth factor, transforming growth factor ? and matrix metalloproteinases, among others, to promote tumor progression. Lysyl oxidase is known to play an important role in hypoxia-dependent cancer cell dissemination and metastasis. Here, we investigated the effects of IR on the expression and secretion of lysyl oxidase (LOX) from tumor cells.MethodsLOX-secretion along with enzymatic activity was investigated in multiple tumor cell lines in response to irradiation. Transwell migration assays were performed to evaluate invasive capacity of naïve tumor cells in response to IR-induced LOX. In vivo studies for confirming IR-enhanced LOX were performed employing immunohistochemistry of tumor tissues and ex vivo analysis of murine blood serum derived from locally irradiated A549-derived tumor xenografts.ResultsLOX was secreted in a dose dependent way from several tumor cell lines in response to irradiation. IR did not increase LOX-transcription but induced LOX-secretion. LOX-secretion could not be prevented by the microtubule stabilizing agent patupilone. In contrast, hypoxia induced LOX-transcription, and interestingly, hypoxia-dependent LOX-secretion could be counteracted by patupilone. Conditioned media from irradiated tumor cells promoted invasiveness of naïve tumor cells, while conditioned media from irradiated, LOX- siRNA-silenced cells did not stimulate their invasive capacity. Locally applied irradiation to tumor xenografts also increased LOX-secretion in vivo and resulted in enhanced LOX-levels in the murine blood serum.ConclusionsThese results indicate a differential regulation of LOX-expression and secretion in response to IR and hypoxia, and suggest that LOX may contribute towards an IR-induced migratory phenotype in sublethally-irradiated tumor cells and tumor progression.

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Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells.

Publications

Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells.

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