TP53 supports basal-like differentiation of mammary epithelial cells by preventing translocation of deltaNp63 into nucleoli.
Multiple observations suggest a cell type-specific role for TP53 in mammary epithelia. We developed an in vitro assay, in which primary mouse mammary epithelial cells (mMECs) progressed from lumenal to basal-like phenotypes based on expression of Krt18 or ΔNp63, respectively. Such transition was markedly delayed in Trp53(-/-) mMECs suggesting that Trp53 is required for specification of the basal, but not lumenal cells. Evidence from human basal-like cell lines suggests that TP53 may support the activity of ΔNp63 by preventing its translocation from nucleoplasm into nucleoli. In human lumenal cells, activation of TP53 by inhibiting MDM2 or BRCA1 restored the nucleoplasmic expression of ΔNp63. Trp53(-/-) mMECs eventually lost epithelial features resulting in upregulation of MDM2 and translocation of ΔNp63 into nucleoli. We propose that TP63 may contribute to TP53-mediated oncogenic transformation of epithelial cells and shed light on tissue- and cell type-specific biases observed for TP53-related cancers.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Pauliina M
PM
Munne
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Yuexi
Y
Gu
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Manuela
M
Tumiati
Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5000, Oulu FIN-90014, Finland.
Ping
P
Gao
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Sonja
S
Koopal
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Sanna
S
Uusivirta
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
Janet
J
Sawicki
Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5000, Oulu FIN-90014, Finland.
Gong-Hong
GH
Wei
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, FIN-00014, Helsinki, Finland.
Sergey G
SG
Kuznetsov
D000818:Animals; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D019313:BRCA1 Protein; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2