Reduction of cell cycle progression in human erythroid progenitor cells treated with tumour necrosis factor alpha occurs with reduced CDK6 and is partially reversed by CDK6 transduction
Chunhua Dai, Ik-Joo Chung, Shazi Jiang, James O. Price,
Sanford B. Krantz,
James O. Price
2 Pathology, Department of Veterans Affairs Medical Center and Vanderbilt University, and
3 The Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
Search for more papers by this authorSanford B. Krantz
Departments of 1 Medicine and
3 The Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
Search for more papers by this authorChunhua Dai, Ik-Joo Chung, Shazi Jiang, James O. Price,
Sanford B. Krantz,
James O. Price
2 Pathology, Department of Veterans Affairs Medical Center and Vanderbilt University, and
3 The Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
Search for more papers by this authorSanford B. Krantz
Departments of 1 Medicine and
3 The Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
Search for more papers by this author Sanford B. Krantz, MD, Department of Medicine–Hematology/Oncology, Vanderbilt University, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232–6307, USA. E-mail: [email protected]
Abstract
Summary. Tumor necrosis factor α (TNFα) potently inhibits the in vitro growth of highly purified human d-6 erythroid colony forming cells (ECFC). Unlike the inhibitory effect of TNFα on other cells, including more immature ECFC, this antiproliferative effect of TNFα is not related to apoptosis because the d-6 cell descendants were morphologically normal, without apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling assay and without caspase activation by Western blots after TNFα treatment. TNFα did not appear to affect the cell cycle distribution, but the cell cycle duration was significantly longer in TNFα-treated cells. DNA synthesis was also significantly reduced by TNFα. Studies of various proteins that regulate the cell cycle showed that cyclin-dependent kinase 6 (CDK6) protein and mRNA levels were concomitantly decreased in the presence of TNFα, suggesting that inhibition of cell growth was related to reduced CDK6. To evaluate this, the CDK6 gene was transferred into ECFC using green fluorescence protein-retrovirus-mediated gene transfer. The results showed that the level of cell growth produced by TNFα was increased by 30% when the cells were transfected with CDK6. Therefore, the modification of cell cycle progression in the presence of TNFα through a reduction of CDK6 is an important mechanism in the TNFα inhibition of human ECFC expansion.
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