PCNA: structure, functions and interactions

Kelman, Zvi

doi:10.1038/sj.onc.1200886

Cited by 812 publications

(602 citation statements)

References 81 publications

(156 reference statements)

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“…7 -9 CDK2 is the catalytic partner of two cyclins involved in S phase progression, cyclin A and E, whereas PCNA plays an essential role in DNA replication as an auxiliary protein of Pol , the enzyme responsible for the replication of chromosomal DNA. In vitro studies have shown that p21 inhibits processive DNA synthesis through a PCNA -dependent mechanism 48 and the formation of Cancer Gene Therapy p21/E2F-1 gene therapy in colon cancer MJ Elliott et al cyclin-CDK complexes. 19 -24 Recently, much attention has been focused on the CDK2 -and PCNA -binding domains of p21 and their importance in facilitating G1 and G2 cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

C-terminal deletion mutant p21WAF1/CIP1 enhances E2F-1–mediated apoptosis in colon adenocarcinoma cells

et al. 2002

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The present study was designed to investigate the efficacy of combination gene therapy using adenoviral vectors expressing gene products shown to possess apoptotic activity: E2F -1 ( Ad -E2F -1 ) and a C -terminal deletion mutant of p21 WAF1 / cIP1 ( Ad -p21 -PCNA ), on growth inhibition and apoptosis of human colon cancer cells in vitro and in vivo. Marked E2F -1 and p21 -PCNA overexpression in response to adenovirus infection was evident by Western blot analysis. IC 25 concentrations of each virus were used for each treatment in vitro to detect cooperative effects on cell death. Coexpression of E2F -1 and p21 -PCNA resulted in an additive effect on cell death compared to infection with either virus alone. Cell cycle analysis, poly( ADP -ribose ) polymerase ( PARP ) cleavage and analysis of cell morphology also revealed that coinfection with both Ad -E2F -1 and Ad -p21 -PCNA enhanced cellular apoptosis compared to either virus alone. Interestingly, E2F -1 protein expression was markedly enhanced in the E2F -1 / p21 -PCNA adenovirus combination compared to Ad -E2F -1 infection alone. However, these same effects were not evident in cells coinfected with Ad -E2F -1 and an adenovirus expressing wild -type human p21 WAF1 / CIP1 ( Ad -p21 WT ). The increase in E2F -1 expression with coexpression of E2F -1 and p21 -PCNA was not a result of increased E2F -1 protein stability, but was related to increased transcriptional activity from the CMV promoter. Cell cycle analysis revealed G1 arrest 72 hours following single -gene therapy with either the wild -type or mutant p21, whereas increased accumulation of cells in G2 / M phase was demonstrated in the E2F -1 -overexpressing cells. In the combined therapies, E2F -1 / p21 -PCNA treatment still resulted in G1 arrest, but E2F -1 was able to counteract the G1 arrest when coinfected with p21 WT . These results provide further evidence of the importance of the p21:PCNA -binding domain in mediating the complex cell cycle interaction between E2F -1 and p21. Simultaneous intratumoral injection of Ad -E2F -1 and Ad -p21 -PCNA dramatically reduced tumor burden of SW620 xenografts compared to either treatment alone in our in vivo model but not in HT -29 colon cancer xenografts. When combined with Ad -p21 -PCNA , E2F -1 adenovirus therapy resulted in approximately 95% decrease in tumor volume of SW620 tumor xenografts compared with controls ( P < .05 ). In conclusion, although simultaneous delivery of E2F -1 and p21 -PCNA transgenes results in increased E2F -1 expression and enhanced apoptosis of both SW620 and HT -29 colon cancer cells in vitro, this combination was only effective in the treatment of SW620 metastatic colon cancer in vivo. This may represent a potentially useful combination gene therapy strategy for metastatic colon cancer.

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Section: Discussionmentioning

confidence: 99%

C-terminal deletion mutant p21WAF1/CIP1 enhances E2F-1–mediated apoptosis in colon adenocarcinoma cells

et al. 2002

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“…We used PCNA, a DNA replication processivity factor, as a marker. Upon progression of S-phase most of the PCNA pool changes its localization from bulk chromatin to the nucleoli and from euchromatin to heterochromatin (Kelman, 1997). Double immunofluorescent staining of an asynchronous population of NIH3T3 cells demonstrated that pW29 does not relocate with PCNA (Fig.…”

Section: Expression and Intracellular Localization Of The Msmcb Msmcmentioning

confidence: 94%

Characterization of the components of the putative mammalian sister chromatid cohesion complex

Darwiche

Freeman

Strunnikov

1999

Gene

109

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Establishing and maintaining proper sister chromatid cohesion throughout the cell cycle are essential for maintaining genome integrity. To understand how sister chromatid cohesion occurs in mammals, we have cloned and characterized mouse orthologs of proteins known to be involved in sister chromatid cohesion in other organisms. The cDNAs for the mouse orthologs of SMC1 S.c. and SMC3 S.c. , mSMCB and mSMCD respectively, were cloned and the corresponding transcripts and proteins were characterized. mSMCB and mSMCD are transcribed at similar levels in adult mouse tissues except in testis, which has an excess of mSMCD transcripts. The mSMCB and mSMCD proteins, as well as the PW29 protein, a mouse homolog of Mcd1p S.c./ Rad21 S.p. , form a complex similar to cohesin in X. laevis. mSMCB, mSMCD and PW29 protein levels show no significant cellcycle dependence. The bulk of the mSMCB, mSMCD and PW29 proteins undergo redistribution from the chromosome vicinity to the cytoplasm during prometaphase and back to the chromatin in telophase. This pattern of intracellular localization suggests a complex role for this group of SMC proteins in chromosome dynamics. The PW29 protein and PCNA, which have both been implicated in sister chromatid cohesion, do not colocalize, indicating that these proteins may not function in the same cohesion pathway. Overexpression of a PW29-GFP fusion protein in mouse fibroblasts leads to inhibition of proliferation, implicating this protein and its complex with SMC proteins in the control of mitotic cycle progression.

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“…PCNA is a processivity factor of DNA polymerase d (pol d), an enzyme involved in both DNA replication and NER (Kelman, 1997). Excess PCNA has been shown to promote DNA synthesis past template lesions (Mozzherin et al, 1996(Mozzherin et al, , 1997.…”

Section: Effect Of Tax On Cellular Dna Repairmentioning

confidence: 99%

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

2005

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PCNA: structure, functions and interactions

Cited by 812 publications

References 81 publications

C-terminal deletion mutant p21WAF1/CIP1 enhances E2F-1–mediated apoptosis in colon adenocarcinoma cells

C-terminal deletion mutant p21WAF1/CIP1 enhances E2F-1–mediated apoptosis in colon adenocarcinoma cells

Characterization of the components of the putative mammalian sister chromatid cohesion complex

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

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