title: The RNA helicase/transcriptional co-regulator, p68 (DDX5), stimulates expression of oncogenic protein kinase, Polo-like kinase-1 (PLK1), and is associated with elevated PLK1 levels in human breast cancers.
abstract: p68 (DDX5) acts both as an ATP-dependent RNA helicase and as a transcriptional co-activator of several cancer-associated transcription factors, including the p53 tumor suppressor. p68 is aberrantly expressed in a high proportion of cancers, but the oncogenic drive for, or the consequences of, these expression changes remain unclear. Here we show that elevated p68 expression in a cohort of human breast cancers is associated significantly with elevated levels of the oncogenic protein kinase, Polo-like kinase-1 (PLK1). Patients expressing detectable levels of both p68 and PLK1 have a poor prognosis, but only if they also have mutation in the TP53 gene (encoding p53), suggesting that p68 can regulate PLK1 levels in a manner that is suppressed by p53. In support of this hypothesis, we show that p68 stimulates expression from the PLK1 promoter, and that silencing of endogenous p68 expression downregulates endogenous PLK1 gene expression. In the absence of functional p53, p68 stimulates the expression of PLK1 both at basal levels and in response to the clinically relevant drug, etoposide. In keeping with a role as a transcriptional activator/co-activator, chromatin immuno-precipitation analysis shows that p68 is associated with the PLK1 promoter, irrespective of the p53 status. However, its recruitment is stimulated by etoposide in cells lacking p53, suggesting that p53 can oppose association of p68 with the PLK1 promoter. These data provide a model in which p68 and p53 interplay regulates PLK1 expression, and which describes the behavior of these molecules, and the outcome of their interaction, in human breast cancer.
authors.affiliation: Division of Cancer Research; University of Dundee; Ninewells Hospital & Medical School; Dundee, UK.
authors.forename: R Sumanth
authors.initials: RS
authors.lastname: Iyer
authors.affiliation: Division of Cancer Research; University of Dundee; Ninewells Hospital & Medical School; Dundee, UK.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Nicol
authors.affiliation: Division of Cancer Research; University of Dundee; Ninewells Hospital & Medical School; Dundee, UK.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Quinlan
authors.affiliation: Division of Cancer Research; University of Dundee; Ninewells Hospital & Medical School; Dundee, UK.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Division of Cancer Research; University of Dundee; Ninewells Hospital & Medical School; Dundee, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Meek
authors.affiliation: Division of Cancer Research; University of Dundee; Ninewells Hospital & Medical School; Dundee, UK.
authors.forename: Frances V
authors.initials: FV
authors.lastname: Fuller-Pace
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000251:Adenosine Triphosphatases; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D053487:DEAD-box RNA Helicases; D005047:Etoposide; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C506749:Ddx5 protein, human
keywords: PLK1; breast cancer; gene expression; p53; p68