title: Ras and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional program.
abstract: The p53 family of transcription factors includes p63, which is a master regulator of gene expression in epithelial cells. Determining whether p63 is tumor-suppressive or tumorigenic is complicated by isoform-specific and cellular context-dependent protein associations, as well as antagonism from mutant p53. ΔNp63 is an amino-terminal-truncated isoform, that is, the predominant isoform expressed in cancer cells of epithelial origin. In HaCaT keratinocytes, which have mutant p53 and ΔNp63, we found that mutant p53 antagonized ΔNp63 transcriptional activity but that activation of Ras or transforming growth factor-β (TGF-β) signaling pathways reduced the abundance of mutant p53 and strengthened target gene binding and activity of ΔNp63. Among the products of ΔNp63-induced genes was dual-specificity phosphatase 6 (DUSP6), which promoted the degradation of mutant p53, likely by dephosphorylating p53. Knocking down all forms of p63 or DUSP6 and DUSP7 (DUSP6/7) inhibited the basal or TGF-β-induced or epidermal growth factor (which activates Ras)-induced migration and invasion in cultures of p53-mutant breast cancer and squamous skin cancer cells. Alternatively, overexpressing ΔNp63 in the breast cancer cells increased their capacity to colonize various tissues upon intracardiac injection in mice, and this was inhibited by knocking down DUSP6/7 in these ΔNp63-overexpressing cells. High abundance of ΔNp63 in various tumors correlated with poor prognosis in patients, and this correlation was stronger in patients whose tumors also had a mutation in the gene encoding p53. Thus, oncogenic Ras and TGF-β signaling stimulate cancer progression through activation of the ΔNp63 transcriptional program.
authors.affiliation: Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Vasilaki
authors.affiliation: Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden.
authors.forename: Masato
authors.initials: M
authors.lastname: Morikawa
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Mizutani
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Hirano
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ehata
authors.affiliation: Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundqvist
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kawasaki
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cedervall
authors.affiliation: Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden. Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.affiliation: Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. miyazono@m.u-tokyo.ac.jp c-h.heldin@licr.uu.se.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.affiliation: Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden. miyazono@m.u-tokyo.ac.jp c-h.heldin@licr.uu.se.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D002465:Cell Movement; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D015689:Oncogene Protein p21(ras)