Caveolin-1 expression is down-regulated in cells transformed by the human papilloma virus in a p53-dependent manner. Replacement of caveolin-1 expression suppresses HPV-mediated cell transformation

B. Razani, Y. Altschuler, Liang Zhu, R. G. Pestell, K. E. Mostov, M. P. Lisanti

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Squamous cell carcinomas of the lung and cervix arise by neoplastic transformation of their respective tissue epithelia. In the case of cervical carcinomas, an increasing body of evidence implicates the human papillomavirus, HPV (types 16 and 18), as playing a pivotal role in this malignant transformation process. The HPV early genes E6 and E7 are known to inactivate the tumor suppressors p53 and Rb, respectively; this leads to disruption of cell cycle regulation, predisposing cells to a cancerous phenotype. However, the role of caveolin-1 (a putative tumor suppressor) in this process remains unknown. Here, we show that caveolin-1 protein expression is consistently reduced in a panel of lung and cervical cancer derived cell lines and that this reduction is not due to hyperactivation of p42/44 MAP kinase (a known negative regulator of caveolin-1 transcription). Instead, we provide evidence that this down-regulation event is due to expression of the HPV E6 viral oncoprotein, as stable expression of E6 in NIH 3T3 cells is sufficient to dramatically reduce caveolin-1 protein levels. Furthermore, we demonstrate that p53 - a tumor suppressor inactivated by E6 - is a positive regulator of caveolin-1 gene transcription and protein expression. SiHa cells are derived from a human cervical squamous carcinoma, harbor a fully integrated copy of the HPV 16 genome (including E6), and show dramatically reduced levels of caveolin-1 expression. We show here that adenoviral-mediated gene transfer of the caveolin-1 cDNA to SiHa cells restores caveolin-1 protein expression and abrogates their anchorage-independent growth in soft agar. Taken together, our results suggest that the HPV oncoprotein E6 down-regulates caveolin-1 via inactivation of p53 and that replacement of caveolin-1 expression can partially revert HPV-mediated cell transformation.

Original languageEnglish (US)
Pages (from-to)13916-13924
Number of pages9
JournalBiochemistry
Volume39
Issue number45
DOIs
StatePublished - Nov 14 2000

Fingerprint

Papillomaviridae
Caveolin 1
Viruses
Caveolins
Human papillomavirus 16
Tumors
Human papillomavirus 18
Genes
Oncogene Proteins
Transcription
Squamous Cell Carcinoma
Proteins
Down-Regulation
Cells
Gene transfer
Neoplasms
NIH 3T3 Cells
Mitogen-Activated Protein Kinase 1
Ports and harbors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Caveolin-1 expression is down-regulated in cells transformed by the human papilloma virus in a p53-dependent manner. Replacement of caveolin-1 expression suppresses HPV-mediated cell transformation. / Razani, B.; Altschuler, Y.; Zhu, Liang; Pestell, R. G.; Mostov, K. E.; Lisanti, M. P.

In: Biochemistry, Vol. 39, No. 45, 14.11.2000, p. 13916-13924.

Research output: Contribution to journalArticle

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AB - Squamous cell carcinomas of the lung and cervix arise by neoplastic transformation of their respective tissue epithelia. In the case of cervical carcinomas, an increasing body of evidence implicates the human papillomavirus, HPV (types 16 and 18), as playing a pivotal role in this malignant transformation process. The HPV early genes E6 and E7 are known to inactivate the tumor suppressors p53 and Rb, respectively; this leads to disruption of cell cycle regulation, predisposing cells to a cancerous phenotype. However, the role of caveolin-1 (a putative tumor suppressor) in this process remains unknown. Here, we show that caveolin-1 protein expression is consistently reduced in a panel of lung and cervical cancer derived cell lines and that this reduction is not due to hyperactivation of p42/44 MAP kinase (a known negative regulator of caveolin-1 transcription). Instead, we provide evidence that this down-regulation event is due to expression of the HPV E6 viral oncoprotein, as stable expression of E6 in NIH 3T3 cells is sufficient to dramatically reduce caveolin-1 protein levels. Furthermore, we demonstrate that p53 - a tumor suppressor inactivated by E6 - is a positive regulator of caveolin-1 gene transcription and protein expression. SiHa cells are derived from a human cervical squamous carcinoma, harbor a fully integrated copy of the HPV 16 genome (including E6), and show dramatically reduced levels of caveolin-1 expression. We show here that adenoviral-mediated gene transfer of the caveolin-1 cDNA to SiHa cells restores caveolin-1 protein expression and abrogates their anchorage-independent growth in soft agar. Taken together, our results suggest that the HPV oncoprotein E6 down-regulates caveolin-1 via inactivation of p53 and that replacement of caveolin-1 expression can partially revert HPV-mediated cell transformation.

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