P53R2: Difference between revisions
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Compare to the M2 subunit, these iron-binding sites are less efficient. This is due to the different conformations that the p53R2 subunit can adopt (stabilization or not of the two helix B and D). | Compare to the M2 subunit, these iron-binding sites are less efficient. This is due to the different conformations that the p53R2 subunit can adopt (stabilization or not of the two helix B and D). | ||
Furthermore the iron is the cofactor of the reaction catalyses by the RNR. The fact that in the p53R2 subunit the iron-binding is less efficient permits to imagine a specific anti-cancer therapy that targets these region, for example the drug [http://en.wikipedia.org/wiki/Deferoxamine deferoxamine mesylate] an iron chelator. Without iron, the reduction of the nucleotides can not take place and this could avoid the proliferation of cancer cells. | Furthermore the iron is the cofactor of the reaction catalyses by the RNR. The fact that in the p53R2 subunit the iron-binding is less efficient permits to imagine a specific anti-cancer therapy that targets these region, for example the drug [http://en.wikipedia.org/wiki/Deferoxamine deferoxamine mesylate] an iron chelator. Without iron, the reduction of the nucleotides can not take place and this could avoid the proliferation of cancer cells. | ||
=='''Target as an anticancer therapy'''== | |||
The p53R2 subunit of the RR acts against cancer in three different ways: the blockage of a MAPK pathway, the repair of the DNA, and the antioxidant activity of p53R2. | |||
=The blockage of a MAPK pathway= | |||
It has been shown that many human tumors require a MAPK pathway to progress and create metastasis. The MAPK pathway using MEK-ERK signaling is the most involved in tumor progression. Indeed, ERK 1 and 2 increase the invasiveness by activating many cytosolic and nuclear substrates which can either increase the transcription of matrix metalloprotease or decrease the transcription of tight junction proteins or disrupt the focal adhesions. The p53R2 subunit of the RR can block this pathway to decrease tumor cell invasion and metastasis. | |||
Experiences from C Piao, M Jin, HB Kim, SM Lee, PN Amatya, J-W Hyun, I-Y Chang and HJ You published in Oncogene 28, show that p53R2 and MEK2 are colocalized in the cytoplasm and that they can bind. This binding is constitutive and depends on the amino acid segment 161 to 206 of p53R2. MEK1 and MEK2 are threonine/tyrosine kinases, they can activate ERK1 and 2 by phosphorylation. The p53R2 regulates negatively the MEK-ERK pathway: it suppresses ERK activation by MEK. p53R2 inhibits tumor cells invasion and metastasis mediated by the blockage of the MEK-ERK pathway and the transcription activity. | |||
=The DNA repair= | |||
The large subunit of the RR: R1 can either interact with R2 or with p53R2 to become catalytically active and produce desoxyribonucleotides for the DNA synthesis. p53R2 is activating by the transcription factor p53. When the cell is stressed, p53 accumulates in the cell and is subjected to post transcriptional modifications which activate the transcription of some genes. This leads to the recruitment of some proteins which will participate to DNA repair. p53R2 helps to repair the DNA by supplying desoxyribonucleotides in a cell where DNA were damaged so it prevents from mutation and cancer. | |||
=p53R2 antioxidant activity= | |||
p53R2 is included in the RR class I which are characterized by a tyrosyl radical coupled with diiron cluster. A protein which possess tyrosyl radicals with binuclear center is known to have an oxidative or a reductive effect. So for the researchers Lijun Xue, Bingsen Zhou, Xiyong Liu, Tieli Wang, Jennifer Shih, Christina Qi, Yvonne Heung and Yun Yen it raises the question of the redox properties of p53R2. They found that p53R2 is an antioxidant which can scavenge H2O2. The mitochondrial membrane is sensible to oxidative damage. H2O2 is a reactive oxygen specie (ROS) which can act on cellular growth and survival and is involved in pathogenesis like cancer. p53R2 prevents the loss of mitochondrial membrane by scavenging H2O2. This process protects cells by maintaining their genomic integrity and prevent from cancer. | |||
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Publications : | Publications : | ||
Smith P. et al, 2009, 2.6 A ° X-ray Crystal Structure of Human p53R2, a p53-Inducible Ribonucleotide Reductase. PMID: [http://www.ncbi.nlm.nih.gov/pubmed/19728742 19728742] | Smith P. et al, 2009, 2.6 A ° X-ray Crystal Structure of Human p53R2, a p53-Inducible Ribonucleotide Reductase. PMID: [http://www.ncbi.nlm.nih.gov/pubmed/19728742 19728742] | ||
Ribonucleotide reductase small subunit p53R2 suppresses MEK-ERK activity by binding to ERK kinase 2 | |||