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

HOUSTON - A metabolic protein that nourishes cancer cells also activates tumor-promoting genes by loosening part of the packaging that entwines DNA to make up chromosomes, a team led by scientists at The University of Texas MD Anderson Cancer Center reports in the Aug. 16 issue of Cell.

Working in cell lines and mouse models of glioblastoma multiforme, the most lethal form of brain tumor, senior author Zhimin Lu, Ph.D., associate professor of Neuro-Oncology at MD Anderson, and colleagues show that pyruvate kinase M2 (PKM2) fuels tumor growth by influencing a histone protein.

DNA is packaged in and spooled around histone proteins. The researchers found that PKM2 tags histone H3 with a phosphate group (one atom of phosphorous, four of oxygen) in a specific location called T11.

'No phosphorylation of H3, no tumor'

This phosphorylation leads to activation of the tumor-promoting genes, increased tumor cell reproduction and formation of tumors, Lu said. "If there's no phosphorylation of H3, there's no tumor. It's that crucial to glioblastoma formation."

An analysis of 85 human glioblastomas indicated that higher levels of PKM2 expression in the cell nucleus and of H3 phosphorylation are correlated with shorter survival. A separate analysis showed higher levels of H3 phosphorylation associated with higher grade tumors in a comparison of 30 low-grade tumor samples and 45 high grade glioblastomas.

"Histone 3-T11 phosphorylation has great potential to serve as both a prognostic marker and a guide for the use of PKM2-inhibiting therapies once they are developed," Lu said.

PKM2 has long been known for its well-established role in aerobic glycolysis - the processing of glucose into energy that solid tumors, glioblastomas in particular, rely on heavily to survive and grow. Lu and colleagues have been teasing out the mechanisms of PKM2's other role - the transcription and activation of genes.

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 proteins that attach phosphate groups to other proteins.


'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

Related medicine news :

1. Normal triglyceride levels in people of African descent may hinder diagnosis of metabolic syndrome
2. Study: Women not getting enough exercise; at risk of developing metabolic syndrome
3. Mutant Kras drives pancreatic cancer maintenance via metabolic pathways
4. VCU researchers identify changes in cholesterol metabolic pathways
5. Metabolic Cooking Review For Karine Losier and Dave Ruel's Diet And Cookbook Program Released
6. Bees shed light on human sweet perception and metabolic disorders
7. Warwick scientists uncover how checkpoint proteins bind chromosomes
8. Specific protein triggers changes in neurons in brain reward center linked to cocaine addiction
9. Unusual protein helps regulate key cell communication pathway
10. Protein prevents DNA damage in the developing brain and might serve as a tumor suppressor
11. RANK protein promotes the initiation, progression and metastasis of human breast cancer
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Metabolic protein wields phosphate group to activate cancer-promoting genes
(Date:6/25/2016)... ... 25, 2016 , ... As a lifelong Southern Californian, Dr. Omkar Marathe earned ... the David Geffen School of Medicine at UCLA. He trained in Internal Medicine at ... fellowship in hematology/oncology at the UCLA-Olive View-Cedars Sinai program where he had the opportunity ...
(Date:6/25/2016)... ... June 25, 2016 , ... Conventional wisdom preaches the benefits of moderation, whether ... latter, setting the bar too high can result in disappointment, perhaps even self-loathing. However, ... their goal. , Research from PsychTests.com reveals that behind the tendency ...
(Date:6/24/2016)... ... June 24, 2016 , ... June 19, 2016 is ... associated with chronic pain and the benefits of holistic treatments, Serenity Recovery Center ... suffering with Sickle Cell Disease. , Sickle Cell Disease (SCD) is a disorder of ...
(Date:6/24/2016)... ... 2016 , ... Global law firm Greenberg Traurig, P.A. announced that 20 Florida ... their peers for this recognition are considered among the top 2 percent of lawyers ... as members of this year’s Legal Elite Hall of Fame: Miami Shareholders Mark ...
(Date:6/24/2016)... ... ... Inc, makers of Topricin and MyPainAway Pain Relief Products, join The ‘Business for a Fair ... hour by 2020 and then adjusting it yearly to increase at the same rate as ... the wage floor does not erode again, and make future increases more predictable. , The ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... , June 23, 2016 Research ... MEMS Devices Medical Market Analysis 2016 - Forecast to 2022" ... The report contains up to date financial data ... analysis. Assessment of major trends with potential impact on the ... analysis of market segmentation which comprises of sub markets, regional ...
(Date:6/23/2016)... 23, 2016 Bracket , a leading clinical ... generation clinical outcomes platform, Bracket eCOA (SM) 6.0, at ... 26 – 30, 2016 in Philadelphia , ... Outcome Assessment product of its kind to fully integrate with ... Bracket eCOA 6.0 is a flexible platform for electronic clinical ...
(Date:6/23/2016)... -- Astellas today announced the establishment of Astellas Farma Colombia (AFC), a new affiliate with operations headquartered in ... . ... ... ... Astellas is ...
Breaking Medicine Technology: