DeltaNp63alpha up-regulates the Hsp70 gene in human cancer.
HSP70, a stress response protein, is known to be a determinant of cell death and cell transformation. We show that different isoforms of p63 have different transcriptional activities on hsp70 genes. DeltaNp63alpha, an abundantly expressed isoform of p63, activates (in vitro and in vivo), whereas TAp63gamma down-regulates the expression of hsp70. We further show that the transactivation domain at the NH(2) terminus of p63 represses, whereas the COOH terminus activates hsp70 transcription. In addition, DeltaNp63alpha regulates transcription of the hsp70 gene through its interaction with the CCAAT binding factor and NF-Y transcription factors which are known to form a complex with the CCAAT box located in the hsp70 promoter. Moreover, DeltaNp63alpha expression correlates with HSP70 expression in all head and neck cancer cell lines. Finally, we show colocalization of DeltaNp63alpha and HSP70 in the epithelium and coexpression of both proteins in 41 primary head and neck cancers. Our study provides strong evidence for the physiologic association between DeltaNp63alpha and hsp70 in human cancer, thus further supporting the oncogenic potential of DeltaNp63alpha.
Wu
Guojun
G
Department of Otolaryngology-Head and Neck Surgery, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA.
Osada
Motonobu
M
Guo
Zhongmin
Z
Fomenkov
Alexey
A
Begum
Shahnaz
S
Zhao
Ming
M
Upadhyay
Sunil
S
Xing
Mingzhao
M
Wu
Feng
F
Moon
Chulso
C
Westra
William H
WH
Koch
Wayne M
WM
Mantovani
Roberto
R
Califano
Joseph A
JA
Ratovitski
Edward
E
Sidransky
David
D
Trink
Barry
B
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D023081:CCAAT-Binding Factor / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D023081:CCAAT-Binding Factor; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins