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[Cancer Research 65, 758-766, February 1, 2005]
© 2005 American Association for Cancer Research

Molecular Biology, Pathobiology and Genetics

{Delta}Np63{alpha} Up-Regulates the Hsp70 Gene in Human Cancer

Guojun Wu1, Motonobu Osada1, Zhongmin Guo1, Alexey Fomenkov1,2, Shahnaz Begum3, Ming Zhao1, Sunil Upadhyay1, Mingzhao Xing5, Feng Wu4, Chulso Moon1, William H. Westra3, Wayne M. Koch1, Roberto Mantovani6, Joseph A. Califano1, Edward Ratovitski1,2, David Sidransky1 and Barry Trink1

Departments of 1 Otolaryngology-Head and Neck Surgery, 2 Dermatology, 3 Pathology, and 4 Medicine, 5 Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland; and 6 Dipartimento di Biologia Animale, Universita di Modena e Reggio Emilia, Modena, Italy

Requests for reprints: David Sidransky and Barry Trink, Division of Head and Neck Cancer Research, 818 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205-2196. Phone: 410-502-5153; Fax: 410-614-1411; E-mail: dsidrans{at}jhmi.edu and btrink{at}jhmi.edu.

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. {Delta}Np63{alpha}, an abundantly expressed isoform of p63, activates (in vitro and in vivo), whereas TAp63{gamma} down-regulates the expression of hsp70. We further show that the transactivation domain at the NH2 terminus of p63 represses, whereas the COOH terminus activates hsp70 transcription. In addition, {Delta}Np63{alpha} 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, {Delta}Np63{alpha} expression correlates with HSP70 expression in all head and neck cancer cell lines. Finally, we show colocalization of {Delta}Np63{alpha} 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 {Delta}Np63{alpha} and hsp70 in human cancer, thus further supporting the oncogenic potential of {Delta}Np63{alpha}.

Key Words: p63 • hsp70 • p53




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