Constitutively active DNA damage checkpoint pathways as the driving force for the high frequency of p53 mutations in human cancer

Abstract Oncogene-induced senescence (OIS) is a barrier for tumor development. Oncogene-dependent DNA damage and activation of the ARF/p53 pathway play a central role in OIS and, accordingly, ARF and p53 are frequently mutated in human cancer. A number of leukemia/lymphoma-initiating oncogenes, however, inhibit ARF/p53 and only infrequently select for ARF or p53 mutations, suggesting the involvement of other tumor-suppressive pathways. We report that NPM-ALK, the initiating oncogene of anaplastic large cell lymphomas (ALCLs), induces DNA damage and irreversibly arrests the cell cycle of primary fibroblasts and hematopoietic progenitors. This effect is associated with inhibition of p53 and is caused by activation of the p16INK4a/pRb tumor-suppressive pathway. Analysis of NPM-ALK lymphomagenesis in transgenic mice showed p16INK4a-dependent accumulation of senescent cells in premalignant lesions and decreased tumor latency in the absence of p16INK4a. Accordingly, human ALCLs showed no expression of either p16INK4a or pRb. Up-regulation of the histone-demethylase Jmjd3 and de-methylation at the p16INK4a promoter contributed to the effect of NPM-ALK on p16INK4a, which was transcriptionally regulated. These data demonstrate that p16INK4a/pRb may function as an alternative pathway of oncogene-induced senescence, and suggest that the reactivation of p16INK4a expression might be a novel strategy to restore the senescence program in some tumors.

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p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G2 DNA Damage Checkpoint in Human Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.00949-09 ◽

2010 ◽

Vol 30 (15) ◽

pp. 3816-3826 ◽

Cited By ~ 37

Author(s):

Mark S. Phong ◽

Robert D. Van Horn ◽

Shuyu Li ◽

Gregory Tucker-Kellogg ◽

Uttam Surana ◽

...

Keyword(s):

Dna Damage ◽

Protein Kinase ◽

Cancer Cells ◽

Human Cancer ◽

Mitogen Activated Protein Kinase ◽

Dna Damage Checkpoint ◽

Checkpoint Control ◽

Independent Manner ◽

Bcl2 Family ◽

Mitogen Activated Protein

ABSTRACT p38 mitogen-activated protein kinase (MAPK) is rapidly activated by stresses and is believed to play an important role in the stress response. While Chk1 is known to mediate G2 DNA damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Here, we have investigated further the roles of p38 and Chk1 in the G2 DNA damage checkpoint in cancer cells. We find that although p38 activation is strongly induced by DNA damage, its activity is not required for the G2 DNA damage checkpoint. In contrast, Chk1 kinase is responsible for the execution of G2 DNA damage checkpoint control in p53-deficient cells. The inhibition of p38 activity has no effect on Chk1 activation and γ-H2AX expression. Global gene expression profiling of cancer cells in response to tumor necrosis factor alpha (TNF-α) revealed that p38 plays a strong prosurvival role through the coordinated downregulation of proapoptotic genes and upregulation of prosurvival genes. We show that the inhibition of p38 activity during G2 DNA damage checkpoint arrest triggers apoptosis in a p53-independent manner with a concurrent decrease in the level of Bcl2 family proteins. Our results suggest that although p38 MAPK is not required for the G2 DNA damage checkpoint function, it plays an important prosurvival role during the G2 DNA damage checkpoint response through the upregulation of the Bcl2 family proteins.

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