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dc.contributor.authorMoussa, Rayan S
dc.contributor.authorKovacevic, Zaklina
dc.contributor.authorBae, Dong-Hun
dc.contributor.authorLane, Darius JR
dc.contributor.authorRichardson, Des R
dc.date.accessioned2021-04-30T00:03:38Z
dc.date.available2021-04-30T00:03:38Z
dc.date.issued2018
dc.identifier.issn0304-4165
dc.identifier.doi10.1016/j.bbagen.2017.10.009
dc.identifier.urihttp://hdl.handle.net/10072/404043
dc.description.abstractBackground: The cyclin-dependent kinase inhibitor, p21, is well known for its role in cell cycle arrest. Novel anti-cancer agents that deplete iron pools demonstrate marked anti-tumor activity and are also active in regulating p21 expression. These agents induce p21 mRNA levels independently of the tumor suppressor, p53, and differentially regulate p21 protein expression depending on the cell-type. Several chelators, including an analogue of the potent anti-tumor agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), have entered clinical trials, and thus, their molecular mechanism of action is crucial to assess. Hence, this investigation examined how several iron chelators transcriptionally regulate p21. Methods: Promoter-deletion constructs; luciferase assays; RT-PCR; western analysis; gene silencing; co-immunoprecipitation. Results: The transcriptional regulation of the p21 promoter by iron chelators was demonstrated to be dependent on the chelator and cell-type examined. The potent anti-cancer chelator, Dp44mT, induced p21 promoter activity in SK-MEL-28 melanoma cells, but not in MCF-7 breast cancer cells. Further analysis of the p21 promoter identified a 50-bp region between − 104 and − 56-bp that was required for Dp44mT-induced activation in SK-MEL-28 cells. This region contained several Sp1-binding sites and mutational analysis of this region revealed the Sp1-3-binding site played a significant role in Dp44mT-induced activation of p21. Further, co-immunoprecipitation demonstrated that Dp44mT induced a marked increase in the interactions between Sp1 and the transcription factors, estrogen receptor-α and c-Jun. Conclusions and general significance: Dp44mT-induced p21 promoter activation via the Sp1-3-binding site and increased Sp1/ER-α and Sp1/c-Jun complex formation in SK-MEL-28 cells, suggesting these complexes were involved in p21 promoter activation.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherElsevier
dc.relation.ispartofpagefrom761
dc.relation.ispartofpageto774
dc.relation.ispartofissue3
dc.relation.ispartofjournalBiochimica et Biophysica Acta (BBA) - General Subjects
dc.relation.ispartofvolume1862
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3214
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsBiophysics
dc.subject.keywordsIron chelator
dc.subject.keywordsMolecular Biology
dc.titleTranscriptional regulation of the cyclin-dependent kinase inhibitor, p21(CIP1/WAF1), by the chelator, Dp44mT
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMoussa, RS; Kovacevic, Z; Bae, D-H; Lane, DJR; Richardson, DR, Transcriptional regulation of the cyclin-dependent kinase inhibitor, p21(CIP1/WAF1), by the chelator, Dp44mT, Biochimica et Biophysica Acta (BBA) - General Subjects, 2018, 1862 (3), pp. 761-774
dcterms.dateAccepted2017-10-11
dc.date.updated2021-04-30T00:02:33Z
gro.hasfulltextNo Full Text
gro.griffith.authorRichardson, Des R.


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