Inverse relationship between p53 and phospho-Chk1 (Ser317) protein expression in UVB-induced skin tumors in SKH-1 mice

Bernard, Jamie J.; Lou, You-Rong; Peng, Qiwei; Li, Tao; Conney, Allan H.; Lü, Yao

doi:10.1016/j.yexmp.2013.10.011

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…This is not totally surprising, as WT p53 can bind TopBP1 (24) (51). Further supporting our results is the observation of an inverse correlation between p53 and Chk1 phosphorylation levels in a UVB-induced mouse skin cancer model (52). The finding prompted the authors to propose that WT p53 might switch off Chk1 phosphorylation, although the mechanism was unknown.…”

Section: Many Hotspot Mutp53 Proteins Hijack the Akt-dependent Regulasupporting

confidence: 85%

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Liu

Lin

Graves

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress. The effect on ATR response caused by mutp53 can be exploited in a synthetic lethality strategy, as depletion of another ATR activator, DNA2, in mutp53-R273H-expressing cancer cells renders cells hypersensitive to cisplatin. Expression of mutp53-R273H also makes cancer cells more sensitive to DNA2 depletion or DNA2 inhibitors. In addition to ATR-activating function during replication stress, TopBP1 interacts with Treslin in a Cdk-dependent manner to initiate DNA replication during normal growth. We find that mutp53 also interferes with TopBP1 replication function. Several contact, but not conformational, mutp53s enhance the interaction between TopBP1 and Treslin and promote DNA replication despite the presence of a Cdk2 inhibitor. Together, these data uncover two distinct mechanisms by which mutp53 enhances DNA replication: (i) Both contact and conformational mutp53s can bind TopBP1 and attenuate the checkpoint response to replication stress, and (ii) during normal growth, contact (but not conformational) mutp53s can override the Cdk2 requirement to promote replication by facilitating the TopBP1/Treslin interaction.ormal cells use various fundamental braking mechanisms to properly respond to environmental cues and coordinate the execution of different phases of cell cycle. Tumor suppressors p53 and pRb are the key regulators for G1 checkpoint, which are frequently lost in many types of cancer (1). Mutations of TP53 are found in half of all human cancers, including nearly all smallcell lung cancers, squamous cell lung cancers, high-grade serous ovarian cancer (2-4), and greater than 80% of glioblastoma and basal-like breast cancer (5, 6). Therefore, understanding the contribution of TP53 mutations in carcinogenesis is very important for the development of new strategies to prevent cancer progression and improve the efficacy of cancer therapy.In addition to the loss of normal p53 function, mutant form of p53 (mutp53) proteins acquire new oncogenic properties (gainof-function, GOF), such as promoting cancer cell proliferation, metastasis, genomic instability, resistance to chemotherapy, etc. (7-9). Among the many mechanisms of mutp53 GOF, the checkpoint activator TopBP1 (topoisomerase IIβ-binding protein) has been identified as a critical mediator for facilitating complex formation between several hotspot mutp53 proteins and either NF-Y or p63/p73 (10). TopBP1 interacts with these mutp53s and NF-Y and promotes mutp53 and p300 recruitment to N...

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Section: Many Hotspot Mutp53 Proteins Hijack the Akt-dependent Regulasupporting

confidence: 85%

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Liu

Lin

Graves

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In another pathway, p53 putatively regulates CHK1 in a positive feedback mechanism. For example, Bernard et al reported that phosphorylation of CHK1 on Ser317 was regulated by p53; thus, p53 may act as a molecular 'on/off' switch for the phosphorylation of CHK1 on Ser317 (29).…”

Section: Discussionmentioning

confidence: 99%

Significant expression of CHK1 and p53 in bladder urothelial carcinoma as potential therapeutic targets and prognosis

et al. 2017

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Abstract. Checkpoint kinase 1 (CHK1) and p53 are involved in cell-cycle checkpoint, and cellular response to DNA damage. CHK1 and p53 are overexpressed in bladder urothelial carcinoma (BUC); however, a clear elucidation on their interaction and influence in the progress of BUC is absent. The aim of the present study was to examine the correlation between CHK1 and p53 in BUC, and analyze their value as therapeutic targets and prognostic indicators in BUC. A clinically annotated cohort of 110 patients with BUC was identified retrospectively. EnVision-based immunohistochemistry and western blot analysis of the aforementioned DNA repair proteins were conducted on formalin-fixed-paraffin-emb edded or frozen tissues from the primary tumor. A total of 45 peritumoral tissue cases were assessed similarly as the control group. In the cohort of 110 patients with BUC, a significant overexpression of CHK1 and p53 was observed in primary compared with the peritumoral tissues (P<0.05). CHK1 and p53 demonstrated a positive correlation in BUC, and both were positively associated with the histological grade, clinical pathological staging, lymphatic metastasis and the 5-year survival rate (P<0.05). However, CHK1 and p53 were not associated with sex, age, tumor diameter, single/multiple sites or incipient/recurrence. The overexpression of CHK1 and p53, and their synergistic interaction were putatively correlated with the physiology of BUC that may be deemed as potential therapeutic targets and prognostic indicators.

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Transcription factor p53 and skin aging

et al. 2017

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Inverse relationship between p53 and phospho-Chk1 (Ser317) protein expression in UVB-induced skin tumors in SKH-1 mice

Cited by 3 publications

References 10 publications

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Significant expression of CHK1 and p53 in bladder urothelial carcinoma as potential therapeutic targets and prognosis

Transcription factor p53 and skin aging

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