p15PAF, a novel PCNA associated factor with increased expression in tumor tissues

Yu, Peiwen; Huang, Betty; Shen, Mary; Lau, Clorinda; Chan, Eva; Michel, Jennifer J. Carlisle; Xiong, Yue; Payan, Donald G.; Luo, Ying

doi:10.1038/sj.onc.1204113

Cited by 106 publications

(151 citation statements)

References 24 publications

(23 reference statements)

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“…Interestingly, it has been reported 17 that p21 cip1 competes with p15 PAF for binding to PCNA, and the expression of 42-fold p21 cip1 protein is sufficient to totally abolish PCNA and p15 PAF association. 17 To confirm such competition in our model, under basal conditions or in cells irradiated with 20 J/m 2 UVC, knock down of p21 was performed in HeLa cells by the transfection of an siRNA specific to p21 (sip21). siLuc was transfected as a control.…”

Section: Resultsmentioning

confidence: 99%

“…15 The physical UV-induced association between p15 PAF and PCNA occurs through a PCNA-binding domain in p15 PAF , and has been described earlier. 16,17 To determine whether p15 PAF -mediated DNA repair requires association with PCNA and thus acts through PCNA, we sought to inhibit this association and evaluate the DNA repair efficiency. Interestingly, it has been reported 17 that p21 cip1 competes with p15 PAF for binding to PCNA, and the expression of 42-fold p21 cip1 protein is sufficient to totally abolish PCNA and p15 PAF association.…”

Section: Resultsmentioning

confidence: 99%

“…It is therefore tempting to speculate that the lack of ATF3 expression contributes to the impaired DNA damage response responsible for oncogenesis. Although upregulation and oncogenic function of p15 PAF has been described in esophageal tumors 17 and in pancreatic cancer, 18 a putative tumor suppressor function has been suggested by its downregulation in several human colorectal tumors and hepatocellular carcinoma. 16,27 As the downregulation does not appear to be related to mutations, 16 it is possible that reduction in the levels of p15 PAF is mediated by the lack of ATF3 expression.…”

Section: Discussionmentioning

confidence: 99%

“…16 p15 PAF binds to PCNA and this binding is enhanced after UV irradiation. 16,17 It is possible that this association, which prevents the binding of p21 cip1 to PCNA, 17 may lead to p21 efficient ubiquitindependent degradation, an essential event for optimal DNA repair through PCNA function. 19 Indeed, recent studies in various cellular models clearly show that downregulation or degradation of p21 after low doses of UV irradiation is required to allow proper DNA repair, [20][21][22][23] whereas a nondegradable mutant of p21 is able to efficiently block this process.…”

Section: Discussionmentioning

confidence: 99%

“…Although p15 PAF downregulation seems to be dependent on the p53-p21 pathway, 18 we show here, that after UV treatment, ATF3 is directly responsible for p15 PAF expression. p15 PAF also known as PCNA-associated factor, KIAA0101 or OEATC-1, 16,17 has been shown to localize to the mitochondria and the nucleus. 16 Its expression is induced upon UV irradiation and it localizes in the cell in the same multiprotein complex as the tumor suppressor p33ING1B.…”

Section: Discussionmentioning

confidence: 99%

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ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15 PAF . We further show that the expressions of ATF3 and p15 PAF is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15 PAF compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15 PAF expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15 PAF expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15 PAF as novel gatekeepers of genomic integrity after UV exposure. Environmental genotoxic stress is one of the major causes of genomic instability. During such a stress, the maintenance of genomic integrity is of crucial importance to allow correct cellular function. The nucleotide excision repair (NER) machinery is responsible for recognition and incision of DNA lesions caused by ultraviolet (UV) irradiation and chemical agents. 1 Proliferating cell nuclear antigen (PCNA) is responsible for recruitment of Pold and, therefore, mediates DNA resynthesis within the site of the lesion. 1 The importance of such machinery is underscored by the numerous human syndromes, such as xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), caused by the mutation of genes involved in DNA repair. Such mutations compromise genomic integrity, and XP and TTD patients are highly photosensitive and prone to develop skin tumors of keratinocyte origin, such as basal and squamous cell carcinoma. Severe defects in the DNA repair mechanism thus impair the apoptotic pathway responsible for destruction of cells that bear the risk of becoming tumorigenic. The correct DNA damage response is therefore of great importance in the maintenance of a UV-inducible anticancer barrier that elicits growth arrest, repair or cell death.Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region leucine zipper (bZIP) family and may be strongly induced in a variety of tissues by different stress signals. 2 Several pathways are responsible for ATF3 induction, such as ATM and Nibrin 1, JNK and NF-kB, in a p53-dependent or -independent manner. 3-5 Induction of ATF3 often correlates with cellular damage, suggesting an important role during the cellular stress response. 6 We have recently reported that the alteration of Egr-1 expression during ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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Nodal yield and survival in oral squamous cancer

Ebrahimi

Zhang

Gao

et al. 2011

Cancer

136

160

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BACKGROUND: Elective neck dissection (END) is commonly used as a staging and therapeutic procedure for oral squamous cell carcinoma (SCC) at high risk of nodal metastases. The authors aimed to determine whether the extent of lymphadenectomy, as defined by nodal yield, is a prognostic factor in this setting. METHODS: A retrospective database review identified 225 patients undergoing END with curative intent for oral SCC between 1987 and 2009. Nodal yield was studied as a categorical variable for association with overall, disease-specific, and disease-free survival in univariate and multivariate analyses. RESULTS: Nodal yield <18 was associated with 5-year overall survival of 51% compared with 74% in those with nodal yield 18 (P ¼ .009). Five-year disease-specific survival rates were 69% in those with <18 nodes and 87% in patients with 18 nodes (P ¼ .022). Similar results were obtained for disease-free survival, with 5-year rates of 44% with <18 nodes versus 71% with 18 nodes (P ¼ .043). After adjusting for the effect of age, nodal status, T stage, and adjuvant radiotherapy on multivariate analysis, nodal yield <18 was associated with reduced overall (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.6; P ¼ .020), disease-specific (HR, 2.2; 95% CI, 1.1-4.5; P ¼ .043), and disease-free survival (HR, 1.7; 95% CI, 1.1-2.8; P ¼ .040). In the pathologically lymph nodenegative subgroup (n ¼ 148), similar results were obtained. CONCLUSIONS: Nodal yield is an independent prognostic factor in patients undergoing END for oral SCC. These results suggest that an adequate lymphadenectomy in this setting should include at least 18 nodes.

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Robust network‐based regularization and variable selection for high‐dimensional genomic data in cancer prognosis

Ren

et al. 2019

Genetic Epidemiology

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In cancer genomic studies, an important objective is to identify prognostic markers associated with patients' survival. Network‐based regularization has achieved success in variable selections for high‐dimensional cancer genomic data, because of its ability to incorporate the correlations among genomic features. However, as survival time data usually follow skewed distributions, and are contaminated by outliers, network‐constrained regularization that does not take the robustness into account leads to false identifications of network structure and biased estimation of patients' survival. In this study, we develop a novel robust network‐based variable selection method under the accelerated failure time model. Extensive simulation studies show the advantage of the proposed method over the alternative methods. Two case studies of lung cancer datasets with high‐dimensional gene expression measurements demonstrate that the proposed approach has identified markers with important implications.

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p15PAF, a novel PCNA associated factor with increased expression in tumor tissues

Cited by 106 publications

References 24 publications

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

Nodal yield and survival in oral squamous cancer

Robust network‐based regularization and variable selection for high‐dimensional genomic data in cancer prognosis

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