Saturday, April 13, 2013

The YES1 gene.

Until we become very familiar with some of the genes, it is very difficult to understand to place new discovered genes in the general context of the cell function.  and yes the YES1 gene is one that one will not see as important until you find out what other gene are in proximity, and what other gene it interact with.
We picked the YES gene randomly, or may be because of its name, but soon we find out that this gene is an important.
The NCBI define this gene as:
"This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22. [provided by RefSeq, Jul 2008]"

From an Oncology stand point, we go from a gene that has a Unique name, very attractive name to potentially a gene that may be important in Sarcoma, a difficult tumor type that we have difficulty treating.  But the exact role of this gene in sarcoma cannot be defined just by the information here!  And frankly, nothing assure us that this is useful target in our quest for the cure.  Yet another clue is given here, its proximity to Thymidylate Synthase.  The relationship as defined here is just proximity and nothing else.  But why that proximity remains an unanswered question.  Are these gene associated in a Linkage?   Do they participate in a similar function? or does the Thymidilate Synthase activity uses the proteins from the YES gene?  Remember Thymidilate Synthase is the molecule used in DNA repair (Folate) and as we shall see YES1 may be involved in a scaffolding important in the preservation of the cell morphology and potentially in the transfer of information to the Nucleus.   The information that there is a pseudogene on chromosome 18, brings to the mind the notion that there is always a bad gene and its corresponding mitigated isoform equivalent.  Somehow nature knows that to bad things there should be a milder version to and frankly we have not used this notion to its full potential!  (the q arm Vs p arm discussion is not far if you know me!)

Just as we become comfortable, Wikipedia adds a new layer to our discussion about the YES1 gene
"Proto-oncogene tyrosine-protein kinase Yes is an enzyme that in humans is encoded by the YES1 gene.[1][2]
This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and belongs to the src family of proteins. This gene lies in close proximity to thymidylate synthase gene on chromosome 18, and a corresponding pseudogene has been found on chromosome 22.[2]

Interactions

YES1 has been shown to interact with Janus kinase 2,[3] CTNND1,[4] RPL10[5] and Occludin.[6]"
"
The Thyrosine Kinase notion brings a careful smile.  We indeed have "beaucoup" of anti-kinases available, and may be we can try these anti/MultiKinase inhibitors in Sarcoma.  Or may be a anti-kinase to yes specifically would be more useful to try in Sarcoma. 
More importantly however is with what gene YES1 interact with.
JAK-2, we are now talking hematologic proliferation.  Now we are deep into Myelofibrosis and and polycythemia.  Now we understand that Sarcoma was probably just a distorsion or quick conclusion that in fact we are talking of stuff downstream the Erythropoietin receptor.  That YES1 is the pathway upstream of JAK2.   The involvement of the CTNND1 (E-cadherin is in the wing) makes sense because the cell needs to stay mobile such as do hematologic malignancies.  It has to stay fluid.  But if we stick to sarcoma, this information will be relevant to metastasis.  Mutation here will involve disease progression and YES1 becomes a clear potential target for the cure!   Or even more importance is my revelation to you that CTNND1 interact with the "crazy gene" FYN we discussed yesterday.  Now YES1 importance becomes even more meaningful because it is upstream the crazy gene!

The story of the YES1 gene becomes more and more interesting when you follow its interaction with RPL10

RPL10

From Wikipedia, the free encyclopedia
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Ribosomal protein L10
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols RPL10; AUTSX5; DXS648; DXS648E; L10; NOV; QM
External IDs OMIM312173 MGI105943 HomoloGene130456 GeneCards: RPL10 Gene
Orthologs
Species Human Mouse
Entrez 6134 434434
Ensembl ENSG00000147403 ENSMUSG00000008682
UniProt P27635 Q6ZWV3
RefSeq (mRNA) NM_001256577 XM_003086757
RefSeq (protein) NP_001243506 XP_003086805
Location (UCSC) Chr HG1497_PATCH:
153.6 – 153.62 Mb
Chr 9:
50.34 – 50.34 Mb

PubMed search [1] [2]
60S ribosomal protein L10 is a protein that in humans is encoded by the RPL10 gene.[1][2]
Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L10E family of ribosomal proteins. It is located in the cytoplasm. In vitro studies have shown that the chicken protein can bind to c-Jun and can repress c-Jun-mediated transcriptional activation, but these activities have not been demonstrated in vivo. This gene was initially identified as a candidate for a Wilms tumor suppressor gene, but later studies determined that this gene is not involved in the suppression of Wilms tumor. This gene has been referred to as 'laminin receptor homolog' because a chimeric transcript consisting of sequence from this gene and sequence from the laminin receptor gene was isolated; however, it is not believed that this gene encodes a laminin receptor. Transcript variants utilizing alternative polyA signals exist. The variant with the longest 3' UTR overlaps the deoxyribonuclease I-like 1 gene on the opposite strand. This gene is co-transcribed with the small nucleolar RNA gene U70, which is located in its fifth intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.[2]
" WIKIPEDIA

-------------------------------NOW YOU ARE BACK INTO SARCOMA, AND ITO BLOKING C-JUN THE CAUSE OF ALL CANCERS CAUSED BY CHRONIC IRRITATIONS AND CHEMICAL EXPOSURES!  NOW YOU ARE THINKING, BLOCKING YES1 CAN BE USED IN CANCER PREVENTION EVEN AGAINST PANCREATIC CANCERS!  NOW YOU ARE THINKING RIBOSOMAL FUNCTION CAN BE ALTERED BY BLOCKING THE YES1.  AND YOU MAY BE RIGHT!

INTERACTION WITH OCCLUDIN ADRESSES THE SHAPE OF THE CELL AND PROVIDE THAT SCAFFOLDING WE WERE TALKING ABOUT.  AND BELIEVE ME IN A ERYTHROCYTE, THE SCAFFOLDING IS CRITICAL (THINK SPHEROCYTOSIS AND ITS PHYSIOLOGIC CONSEQUENCE).

IT IS JUST A MATTER OF WHEN YOU WANT TO STOP FOLLOWING THE MONEY.

And yes, the YES1 gene is like a gift that keeps on giving
and may be an important target in some described cancers (see above!)

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