Mitogenic effects of the up-regulation of minichromosome maintenance proteins in anaplastic thyroid carcinoma.
BACKGROUND
Anaplastic thyroid carcinomas (ATC) are among the most aggressive human malignancies and are characterized by high mitotic activity. Minichromosome maintenance proteins (MCM) 2-7 are required to initiate eukaryotic DNA replication, and their overexpression has been associated with dysplasia and malignancy.


OBJECTIVE
In an attempt to cast light on the mechanisms governing ATC, we evaluated MCM5 and MCM7 expression in human normal, papillary (PTC), and anaplastic thyroid samples, as well as in primary culture cells and transgenic mouse models.


RESULTS
MCM5 and MCM7 expression was high in 65% of ATC and negligible in normal thyroid tissue and papillary thyroid carcinomas. In ATC, high MCM5 and MCM7 expression was paralleled by high levels of MCM2 and MCM6. An analysis of human ATC primary cell cultures and of a transgenic mouse model of ATC confirmed these findings. An increased transcription rate accounted for MCM7 up-regulation, because the activity of the MCM7 promoter was more than 10-fold higher in ATC cells compared with normal thyroid cells. Adoptive overexpression of wild-type p53, but not of its inactive (R248W and R273H) mutants, strongly down-regulated transcription from the MCM7 promoter, suggesting that p53 knock-out contributes to MCM7 up-regulation in ATC. Treatment with small inhibitory duplex RNAs, which decrease MCM7 protein levels, reduced the rate of DNA synthesis in ATC cells.


CONCLUSIONS
MCM proteins are overexpressed in ATC and sustain the high proliferative capacity of ATC cells.
Guida
Teresa
T
Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, via S. Pansini 5, 80131 Naples, Italy.
Salvatore
Giuliana
G
Faviana
Pinuccia
P
Giannini
Riccardo
R
Garcia-Rostan
Ginesa
G
Provitera
Livia
L
Basolo
Fulvio
F
Fusco
Alfredo
A
Carlomagno
Francesca
F
Santoro
Massimo
M
D000818:Animals; D002291:Carcinoma, Papillary / Q000503:physiopathology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D064111:Minichromosome Maintenance Complex Component 2; D064151:Minichromosome Maintenance Complex Component 6; D064168:Minichromosome Maintenance Complex Component 7; D008934:Mitogens / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D013964:Thyroid Neoplasms / Q000503:physiopathology*; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C489423:MCM5 protein, human; D008934:Mitogens; D009687:Nuclear Proteins; D012333:RNA, Messenger; D004247:DNA; C084859:MCM2 protein, human; C103258:MCM6 protein, human; C101624:MCM7 protein, human; D064111:Minichromosome Maintenance Complex Component 2; D064151:Minichromosome Maintenance Complex Component 6; D064168:Minichromosome Maintenance Complex Component 7