Wednesday, March 20, 2013

GENES IN CHORIOCARCINOMA

The major interest here at the CRBCM is of course obtaining a cure.  There is therefore a strong interest in knowing more about cancers that are deemed curable today.  Studying the genes known in these diseases could provide some clues to their susceptibility to chemotherapy drugs available today. Below are some of the genes for CHORIOCARCINOMA:

1. NECC1 on 4q11  (notice the "q" as this may be bad news)

This is a gene of differentiation.  And from what we have gathered, it is a gene that codes for a Core Binding Factor like Molecule, these complexes of major proteins with various functions put together to direct cellular functions in directions.  The proteins globally function as regulators of other cellular functions. These proteins are sequentially positioned in the CBF to drive into some directions.  Most of the times, the CBF has a portion that attaches to the DNA.  The attachment could silence the DNA.  The silenced DNA here seems to block Cardiac differentiation and forces the direction of activity toward syncytial trophoblastic differentiation.  This is why this gene is expressed in normal placenta.  In choricarcinoma, dedifferentiation occurs and NECC1 is mutated and silenced.  This is called a suppressor gene as it relates to Cardiac muscle differentiation, but clearly not for the tumor from what we gathered.  The Mutation will have to occur at the "q" location.  We will look further to establish if the "p" of this gene is located on chromosome 7.
Desactivation of NECC1 leads to cardiac hypertrophy.  Being a CBF like molecule, it may solicit Histone deacetyl transferases as part of its nuclear activity.  We still are unclear whether it is at the center of the pathogenesis of choriocarcinoma or not!
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2.CSH1
The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones and plays an important role in growth control. The gene is located at the growth hormone locus on chromosome 17 along with four other related genes in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. Although the five genes share a remarkably high degree of sequence identity, they are expressed selectively in different tissues. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed mainly in the placenta and utilizes multiple transcription initiation sites. Expression of the identical mature proteins for chorionic somatomammotropin hormones 1 and 2 is upregulated during development, although the ratio of 1 to 2 increases by term. Mutations in this gene result in placental lactogen deficiency and Silver-Russell syndrome. [provided by RefSeq, Jul 2008]"
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3. IGFR1

"Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene.[1][2] IGF-1 has also been referred to as a "sulfation factor"[3] and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s.
IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults.
 IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.
Other IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity."(Wikipedia)

IGFR1  amplification is used in autocrine faction to drive cancer growth, it acts here a as a TGF.
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4. CHFR
E3 ubiquitin-protein ligase CHFR is an enzyme that in humans is encoded by the CHFR gene.[1][2][3]
(wikipedia)

"One protein that has been suggested to be part of the antephase checkpoint is Chfr (checkpoint protein with an FHA domain and ring finger; Scolnick and Halazonetis, 2000), a ubiquitin ligase that is down-regulated in several cell lines through methylation of its promoter (Mizuno et al., 2002). Chfr was originally reported to delay progress to prometaphase in the presence of colcemid (Scolnick and Halazonetis, 2000), and cells were surprisingly described as delaying with high cyclin B1-Cdk1 activity (Scolnick and Halazonetis, 2000), which conflicted with a role as part of the antephase checkpoint because cyclin B1-Cdk1 is fully activated only in late prophase. However, in Xenopus laevis extracts, Chfr is able to delay the activation of cyclin B-Cdk1, apparently by targeting the Polo-like kinase, Plx, for degradation by the proteasome (Kang et al., 2002), thereby preventing the activation of the Cdc25 phosphatase that activates Cdk1. Chfr has also been reported to affect Polo-like kinase levels in human cells in response to DNA damage (Shtivelman, 2003). But whether Chfr does target Polo for degradation or not is debatable because Chfr has been shown to conjugate ubiquitin via its lysine 63 residue (Bothos et al., 2003) that normally acts in signal transduction, especially for stress signals (Deng et al., 2000; Ulrich and Jentsch, 2000; Hofmann and Pickart, 2001; Pickart, 2001; Wang et al., 2001), rather than to target proteins to the proteasome."
Matsusaka and pines suggested.

CERTAINLY DOWN REGULATION HERE OPEN THE DOOR TO USE OF VELCADE OR THE PROTEASOME INHIBITORS.


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5. MUC3A"Associations of distinct variants of the intestinal mucin gene MUC3A with ulcerative colitis and Crohn's disease [1]." (WIKI) Its gene is located at 7q22  (notice the q) it has a prognosis value
But we also know that MUC1 will be more important in this cancer and shield by its mucinous product cell from cancer watching cells.

James Gum et al "Mucinous cancers are generally more extensive at diagnosis. Membrane mucins are an important class of glycoproteins with diverse structures and functions. These molecules contain extracellular domains that serve as a scaffold for O-glycosylation. The O-glycans associated with membrane mucins are thought to function in cytoprotection and have been demonstrated to confer anti-adhesion properties upon cells (1). This latter characteristic may play a role in the dissemination and spread of cancer cells. In addition to conferring these electrostatic/physical properties upon cells, membrane mucins can anchor carbohydrate moieties with specific functions. Selectin ligands associated with membrane mucin glycans, for example, play a role in cancer cell extravasation during metastases (2). Certain membrane mucins function in signal transduction as well (35). Several membrane mucins also serve as clinically important tumor antigens (6, 7)."




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6. TAF7

TAF7

From Wikipedia, the free encyclopedia
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TAF7 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 55kDa
Identifiers
Symbols TAF7; TAF2F; TAFII55
External IDs OMIM600573 MGI1346348 HomoloGene11768 GeneCards: TAF7 Gene
RNA expression pattern
PBB GE TAF7 201023 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6879 24074
Ensembl ENSG00000178913 ENSMUSG00000051316
UniProt Q15545 Q9R1C0
RefSeq (mRNA) NM_005642 NM_175770
RefSeq (protein) NP_005633 NP_786964
Location (UCSC) Chr 5:
140.7 – 140.7 Mb
Chr 18:
37.64 – 37.64 Mb

PubMed search [1] [2]
Transcription initiation factor TFIID subunit 7 also known as TAFII55 is a protein that in humans is encoded by the TAF7 gene.[1]
The intronless gene for this transcription coactivator is located between the protocadherin beta and gamma gene clusters on chromosome 5. The protein encoded by this gene is a component of the TFIID protein complex, a complex which binds to the TATA box in class II promoters and recruits RNA polymerase II and other factors. This particular subunit interacts with the largest TFIID subunit, as well as multiple transcription activators. The protein is required for transcription by promoters targeted by RNA polymerase II.[2]
TAFII55_N
Identifiers
Symbol TAFII55_N
Pfam PF04658
InterPro IPR006751
The general transcription factor, TFIID, consists of the TATA-binding protein (TBP) associated with a series of TBP-associated factors (TAFs) that together participate in the assembly of the transcription preinitiation complex. TAFII55 binds to TAFII250 and inhibits its acetyltransferase activity. The exact role of TAFII55 is currently unknown but studies have shown that it interacts with the C-jun pathway.[3] The conserved region is situated towards the N-terminal of the protein.[4] This entry talks about the N-terminal domain.
TAF7 interacts with TATA which



The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene promoters.[1] TBP, along with a variety of TBP-associated factors, make up the TFIID, a general transcription factor that in turn makes up part of the RNA polymerase II preinitiation complex.[2] As one of the few proteins in the preinitiation complex that binds DNA in a sequence-specific manner, it helps position RNA polymerase II over the transcription start site of the gene. However, it is estimated that only 10-20% of human promoters have TATA boxes. Therefore, TBP is probably not the only protein involved in positioning RNA polymerase II.
TBP is involved in DNA melting (double strand separation) by bending the DNA by 80° (the AT-rich sequence to which it binds facilitates easy melting). The TBP is an unusual protein in that it binds the minor groove using a β sheet.
Another distinctive feature of TBP is a long string of glutamines in the N-terminus of the protein. This region modulates the DNA binding activity of the C-terminus, and modulation of DNA-binding affects the rate of transcription complex formation and initiation of transcription. Mutations that expand the number of CAG repeats encoding this polyglutamine tract, and thus increase the length of the polyglutamine string, are associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease.[3]

BASICALLY INITIATE OR PARTICIPATE IN THE INITIATION OF OF TRANSCRIPTION/TRANSLATION
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8. CDC123
9. PSMD
10. HAS2
11. CD44  a member of the EZRIN/S100P/ Villin -Complex
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12. S100P 

S100P

From Wikipedia, the free encyclopedia
Jump to: navigation, search
S100 calcium binding protein P

PDB rendering based on 1j55.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols S100P; MIG9
External IDs OMIM600614 HomoloGene81743 GeneCards: S100P Gene
RNA expression pattern
PBB GE S100P 204351 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6286 n/a
Ensembl ENSG00000163993 n/a
UniProt P25815 n/a
RefSeq (mRNA) NM_005980 n/a
RefSeq (protein) NP_005971 n/a
Location (UCSC) Chr 4:
6.69 – 6.7 Mb
n/a
PubMed search [1] n/a
Protein S100-P is a protein that in humans is encoded by the S100P gene.[1][2][3]
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 4p16. This protein, in addition to binding Ca2+, also binds Zn2+ and Mg2+. This protein may play a role in the etiology of prostate cancer.[3]

Interactions

S100P has been shown to interact with EZR.[4] which this protein serves as an intermediate between the plasma membrane and the actin cytoskeleton. It plays a key role in cell surface structure adhesion, migration, and organization.[2]

Interactions

VIL2 has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2,[3][4] Merlin,[5] SDC2,[6] CD43,[7] Fas ligand,[8][9] VCAM-1,[10] S100P,[11] ICAM3,[12][13] ICAM-1,[12] Sodium-hydrogen antiporter 3 regulator 1,[14][15] ICAM2,[12] Moesin,[8][16][17] PALLD[18] and PIK3R1.[19]

Given the multitude of interactions the EZERIN appears a critical molecules for signal propagation intra and extra-cellularly.  EZRIN the Villin (Vilain) comes into everything.  In the endothelium,  This complex of molecules is " involved in the generation and maintenance of the anchoring structure. These results provide the first characterization of an endothelial docking structure that plays a key role in the firm adhesion of leukocytes to the endothelium during inflammation." 
This is a basis for novel anti-inflammatory strategy.
It also interact with the so called Peripheral proteins of which  "some are water-soluble proteins and associate with lipid bilayers irreversibly and can form transmembrane alpha-helical or beta-barrel channels. Such transformations occur in pore forming toxins such as colicin A, alpha-hemolysin, and others. They may also occur in BcL-2 like protein , in some amphiphilic antimicrobial peptides , and in certain annexins . These proteins are usually described as peripheral as one of their conformational states is water-soluble or only loosely associated with a membrane.[11]"

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13. delta-like1
14. STOX1
15. JAK/STAT1
16. GCM1
Chorion-specific transcription factor GCMa is a protein that in humans is encoded by the GCM1 gene.[1][2]
This gene encodes a DNA-binding protein with a gcm-motif (glial cell missing motif). The encoded protein is a homolog of the Drosophila glial cells missing gene (gcm). This protein binds to the GCM-motif (A/G)CCCGCAT, a novel sequence among known targets of DNA-binding proteins. The N-terminal DNA-binding domain confers the unique DNA-binding activity of this protein.[2]WIKIPEDIA


Chou et al "the activity of GCMa can be post-translationally regulated by protein phosphorylation, ubiquitination, and acetylation, it is unknown whether GCMa activity can be regulated by sumoylation. In this report, we investigated the role of sumoylation in the regulation of GCMa activity. We demonstrated that Ubc9, the E2 component of the sumoylation machinery...Our study demonstrates that GCMa is a new sumoylation substrate and its activity is down-regulated by sumoylation."

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18. Cx31: Connexin, important in cell adhesion and embryogenesis.  In adult Mutation at Cx31 lead to sensory neural deafness as it contribute to synaptic integrity and Monocyte.  A legitimate secondary target in blood disease.
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also we will include
19. Endoglin
20. Syncitin
21. HCG
22. Connexin 31
23. E-Cadherin

Lets go to work!

Another thing to look at is the propensity in these diseases to develop thrombosis on BEP treatment!
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