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The Journal of Neuroscience, April 19, 2006, 26(16):4329-4337; doi:10.1523/JNEUROSCI.0382-06.2006

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Cellular/Molecular
Mild Hypoxia Promotes Survival and Proliferation of SOD2-Deficient Astrocytes via c-Myc Activation

Jing Liu, Purnima Narasimhan, Yong-Sun Lee, Yun Seon Song, Hidenori Endo, Fengshan Yu, and Pak H. Chan

Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305-5487

Correspondence should be addressed to Dr. Pak H. Chan, Neurosurgical Laboratories, Stanford University, 1201 Welch Road, MSLS #P304, Stanford, CA 94305-5487. Email: phchan{at}stanford.edu

Mouse astrocytes deficient in the mitochondrial form of manganese superoxide dismutase (SOD2) do not survive in culture under atmospheric air with 20% oxygen (O₂), which is a common condition for cell cultures. Seeding the cells and maintaining them under mild hypoxic conditions (5% O₂) circumvents this problem and allows the cells to grow and become confluent. Previous studies from our laboratory showed that this adaptation of the cells was not attributable to compensation by other enzymes of the antioxidant defense system. We hypothesized that transcriptional activity and upregulation of genes other than those with an antioxidant function are involved. Our present study shows that c-Myc was significantly induced and that it inhibited p21 and induced proteins such as cyclin-dependent kinases, cyclin D, and cyclin E, which are involved in the cell cycle process, along with phosphorylation of the retinoblastoma protein and Cdc2 (cell division cycle 2). These mechanisms contribute to cell proliferation. Small interfering RNA of c-Myc, however, blocked proliferation of SOD2 homozygous (SOD2–/–) astrocytes under mild hypoxia consisting of 5% O₂, whereas it did not affect the growth of wild-type astrocytes. Our results indicate that c-Myc plays a critical role in hypoxia-induced proliferation and survival of SOD2–/– astrocytes by overcoming injury caused by oxidative stress.

Key words: oxidative stress; mitochondria; manganese superoxide dismutase; hypoxia; c-Myc; cyclin-dependent kinases

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Received Oct. 3, 2005; revised March 16, 2006; accepted March 16, 2006.

Correspondence should be addressed to Dr. Pak H. Chan, Neurosurgical Laboratories, Stanford University, 1201 Welch Road, MSLS #P304, Stanford, CA 94305-5487. Email: phchan{at}stanford.edu

This article has been cited by other articles:

				K. Yekkala and T. A. Baudino Inhibition of Intestinal Polyposis with Reduced Angiogenesis in ApcMin/+ Mice Due to Decreases in c-Myc Expression Mol. Cancer Res., December 1, 2007; 5(12): 1296 - 1303. [Abstract] [Full Text] [PDF]

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