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Metabolic protein wields phosphate group to activate cancer-promoting genes
Date:8/16/2012

It all starts with EGFR

When the epidermal growth factor receptor (EGFR) on the cell's membrane is activated by a growth factor, the PKM2 protein moves into the cell nucleus, where it binds to the promoter regions of genes. Other proteins called transcription factors attach to a gene's promoter region to activate it.

Cancer cells have high levels of EGFR on the cell surface, relaying growth signals from outside the cell inside. EGFR is itself a target of some cancer drugs.

A series of experiments by the research team uncovered the following molecular steps:

  • After EGFR activation, PKM2 binds to histone H3 and attaches a phosphate group at T11.

  • This separates another protein called histone deacetylase 3 (HDAC3) from the promoter regions of the genes CCND1 and MYC. HDACs block gene activation.

  • With the HDACs gone, histone H3 acquires an acetyl group, which facilitates gene activation.

"This series of events only occurs when H3 is phosphorylated by PKM2," Lu said.

Blocking phosphorylation prevents brain tumors in mice

CCND1 expresses the protein cyclin D1, a cell cycle regulator. The MYC gene is frequently mutated in cancer, leading to overexpression of the transcription factor Myc, which in turn causes unregulated expression of many other genes.

Mouse experiments of EGFR-driven glioblastoma using reconstituted H3 histones, one normal and one with a mutant version of H3-T11A to prevent phosphorylation by PKM2, confirmed the relationship. Mice injected with normal, or wild type, H3, had an average tumor volume of nearly 40 cubic millimeters, while those with disabled T11A, blocking the phosphorylation point for PKM2, had no tumors.

"Our findings establish PKM2 as a histone kinase, which directly regulates gene transcription and controls cell cycle progression and proliferation of tumor cells" Lu said. Kinases are a class of pr
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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