The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5′-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62’s aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.

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Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-08-1037 ◽

2009 ◽

Vol 8 (6) ◽

pp. 1473-1483 ◽

Cited By ~ 60

Author(s):

Zanna Beharry ◽

Marina Zemskova ◽

Sandeep Mahajan ◽

Fengxue Zhang ◽

Jian Ma ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Protein Kinase ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Kinase Activity ◽

Protein Kinase Activity ◽

Prostate Cancer Cells ◽

Induce Cell Cycle Arrest ◽

Cycle Arrest

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Nuclear Accumulation of IE62, the Varicella-Zoster Virus (VZV) Major Transcriptional Regulatory Protein, Is Inhibited by Phosphorylation Mediated by the VZV Open Reading Frame 66 Protein Kinase

Journal of Virology ◽

10.1128/jvi.74.5.2265-2277.2000 ◽

2000 ◽

Vol 74 (5) ◽

pp. 2265-2277 ◽

Cited By ~ 61

Author(s):

Paul R. Kinchington ◽

Karen Fite ◽

Stephanie E. Turse

Keyword(s):

Protein Kinase ◽

Varicella Zoster Virus ◽

Nuclear Localization ◽

Kinase Activity ◽

Open Reading Frame ◽

Nuclear Accumulation ◽

Protein Kinase Activity ◽

Reading Frame ◽

Varicella Zoster ◽

In Cells

ABSTRACT IE62, the major transcriptional activator protein encoded by varicella-zoster virus (VZV), locates to the nucleus when expressed in transfected cells. We show here that cytoplasmic forms of IE62 accumulate in transfected and VZV-infected cells as the result of the protein kinase activity associated with VZV open reading frame 66 (ORF66). Expression of the ORF66 protein kinase but not the VZV ORF47 protein kinase impaired the ability of coexpressed IE62 to transactivate promoter-reporter constructs. IE62 that was coexpressed with the ORF66 protein accumulated predominantly in the cytoplasm, whereas the normal nuclear localization of other proteins was not affected by the ORF66 protein. In cells infected with VZV, IE62 accumulated in the cytoplasm at late times of infection, whereas in cells infected with a VZV recombinant unable to express ORF66 protein (ROka66S), IE62 was completely nuclear. Point mutations introduced into the predicted serine/threonine catalytic domain and ATP binding domain of ORF66 abrogated its ability to influence IE62 nuclear localization, indicating that the protein kinase activity was required. The region of IE62 that was targeted by ORF66 was mapped to amino acids 602 to 733. IE62 peptides containing this region were specifically phosphorylated in cells coexpressing the ORF66 protein kinase and in cells infected with wild-type VZV but were not phosphorylated in cells infected with ROka66S. We conclude that the ORF66 protein kinase phosphorylates IE62 to induce its cytoplasmic accumulation, most likely by inhibiting IE62 nuclear import.

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