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J. Biol. Chem., Vol. 280, Issue 18, 18033-18041, May 6, 2005

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Manganese Superoxide Dismutase Protects the Proliferative Capacity of Confluent Normal Human Fibroblasts^*

Ehab H. Sarsour, Manjula Agarwal, Tej K. Pandita, Larry W. Oberley, and Prabhat C. Goswami¶

From the Free Radical and Radiation Biology Program, Department of Radiation Oncology, the University of Iowa, Iowa City, Iowa 52242 and the Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63108

We tested the hypothesis that manganese superoxide dismutase (MnSOD), an antioxidant enzyme, regulates the proliferative potential of confluent human fibroblasts. Normal human skin (AG01522) and lung (WI38, CCL-75) fibroblasts kept in confluence (>95% G₀/G₁) showed a significant decrease in their capacity to re-enter the proliferation cycle after 40-60 days. The inhibition of re-entry was accompanied with the age-dependent increase of p16 protein levels in the confluent culture. Adenoviral mediated overexpression of MnSOD during confluent growth suppressed p16, enhanced p21 protein accumulation, and protected fibroblasts against the loss of proliferation potential. Increases in p21 protein levels in MnSOD overexpressing confluent fibroblasts were independent of p53 protein levels. p53 protein levels did not change in control, replication-defective adenovirus containing an insertless vector (AdBgl II), or AdMnSOD-infected confluent cells cultured for 20 and 60 days. In addition, MnSOD-induced protection of the proliferation capacity of confluent fibroblasts was independent of their telomerase activity. However, telomerase-transformed fibroblasts showed increased MnSOD expression in confluent growth, maintaining their capacity to re-enter the proliferation cycle. Although inactivation of the retinoblastoma protein in cells subcultured from the 60-day confluent control, AdBgl II-, and AdMnSOD-infected fibroblasts was identical, only MnSOD-overexpressing cells showed a higher percentage of S-phase. These results support the hypothesis that a redox-sensitive checkpoint regulated the progression of fibroblasts from G₀/G₁ to S-phase.

Received for publication, February 22, 2005

^* This work was supported by American Cancer Society Grant IRG77-004-25 (to P. C. G.) and National Institutes of Health Grants 5PO1 CA66081 (to L. W. O.) and NS34736 (to T. K. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Free Radical and Radiation Biology Program, Dept. of Radiation Oncology, B180 Medical Laboratories, University of Iowa, Iowa City, IA 52242. Tel.: 319-384-4466; Fax: 319-335-8039; E-mail: prabhat-goswami{at}uiowa.edu.

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