Effects of adenovirus-mediated p16(INK4A) expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells

Caroline Craig, Min Kim, Ekta Ohri, Robert Wersto, Dai Katayose, Zhuangwu Li, Yung Hyun Choi, Bali Mudahar, Shiv Srivastava, Prem Seth, Kenneth Cowan

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

We constructed an adenoviral vector containing human p16 cDNA in order to evaluate the cytotoxic effects of exogenous p16 expression on cancer cell proliferation and to explore the potential use of p16 in cancer gene therapy. Following infection of human breast (MCF-7, MDA-MB-231, and BT549), osteosarcoma (U-2 OS and Saos-2), cervical (C33a), and lung cancer (H358) cell lines with the recombinant adenovirus Adp16, high levels of p16 expression were observed in all cell lines. Cancer cell lines which were mutant or null for p16 but wild-type for the retinoblastoma gene product (pRb) (MCF-7, MDA-MB-231, BT549 and U-2 OS) were 7-22-fold more sensitive to the cytotoxic effects of Adp16 than to a control virus. In contrast, cancer cell lines which were wild-type for p16 but mutant or null for pRb (Saos-2, C33a and H358) were < threefold more sensitive to Adp16 when compared to a control virus. Analysis of 5-bromodeoxyuridine incorporation into DNA following infection with Adp16 showed a loss of S phase in those cell lines which were null or mutant for p16 but expressed a functional pRb. This cell cycle arrest was associated with binding of the p16 protein to cyclin-dependent kinase 4 and dephosphorylation of pRb. In contrast, human cancer cell lines expressing a wild-type p16 and a mutant pRb or no pRb showed no substantial loss of S phase following Adp16 infection. Based on these studies, we conclude that p16-mediated cytotoxicity is tightly associated with the presence of functional pRb in human cancer cells, and that tumor cells which are mutant or null for p16 are candidates for Adp16 mediated cancer gene therapy.

Original languageEnglish (US)
Pages (from-to)265-272
Number of pages8
JournalOncogene
Volume16
Issue number2
DOIs
StatePublished - Jan 15 1998

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Cyclin-Dependent Kinase Inhibitor p16
Cell Cycle Checkpoints
Adenoviridae
Cell Line
Neoplasms
Neoplasm Genes
S Phase
Genetic Therapy
Infection
Cyclin-Dependent Kinase 4
Retinoblastoma Genes
Viruses
Osteosarcoma
Bromodeoxyuridine
Uterine Cervical Neoplasms
Lung Neoplasms
Carrier Proteins
Breast
Complementary DNA
Cell Proliferation

Keywords

  • Adenovirus
  • Breast cancer
  • Cyclin dependent kinase inhibitors
  • Gene therapy
  • p16

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Effects of adenovirus-mediated p16(INK4A) expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells. / Craig, Caroline; Kim, Min; Ohri, Ekta; Wersto, Robert; Katayose, Dai; Li, Zhuangwu; Choi, Yung Hyun; Mudahar, Bali; Srivastava, Shiv; Seth, Prem; Cowan, Kenneth.

In: Oncogene, Vol. 16, No. 2, 15.01.1998, p. 265-272.

Research output: Contribution to journalArticle

Craig, C, Kim, M, Ohri, E, Wersto, R, Katayose, D, Li, Z, Choi, YH, Mudahar, B, Srivastava, S, Seth, P & Cowan, K 1998, 'Effects of adenovirus-mediated p16(INK4A) expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells', Oncogene, vol. 16, no. 2, pp. 265-272. https://doi.org/10.1038/sj.onc.1201493
Craig, Caroline ; Kim, Min ; Ohri, Ekta ; Wersto, Robert ; Katayose, Dai ; Li, Zhuangwu ; Choi, Yung Hyun ; Mudahar, Bali ; Srivastava, Shiv ; Seth, Prem ; Cowan, Kenneth. / Effects of adenovirus-mediated p16(INK4A) expression on cell cycle arrest are determined by endogenous p16 and Rb status in human cancer cells. In: Oncogene. 1998 ; Vol. 16, No. 2. pp. 265-272.
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