User:Michelle.chen92/sandbox

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Proto-oncogene protein Wnt-1

embryogenesis. [2]

Wnt-1 is a secreted

amino acids in length with conserved pattern of 23-25 cysteine residues across species.[3]

During embryonic development, Wnt-1 plays a role in generation of

tumorogenesis.[3]

Wnt signals through

beta-catenin, which leads to the increased expression of 50+ genes.[7]

History of Discovery

Wnt-1 protein can be referred to as Int-1 or Wg in literature, varying by the organism studied and the time of research. Int-1 (Integration site-1) was first described by Nusse and Varmus in 1982 as the

ortholog gene in Drosophila melanogaster was described as Wg (Wingless), from the wingless phenotype of mutants. [9] To reduce confusion, Int-1 and Wg were combined and renamed as Wnt-1 around the 1990s.[10]

Role in Embryonic Development

Central Nervous System Development

Wnt-1 is required for proper formation of the

phenotypes: some die at birth lacking an entire cerebellum and parts of the midbrain, while some live through adulthood suffering from ataxia and lacking the anterior half of the cerebellum.[5] The malformed parts of the brain in Wnt-1 mutants correspond to not only the region where Wnt-1 would normally be highly expressed, but also the surrounding tissues.[11] This suggests Wnt-1 protein’s importance in inducing development of surrounding tissues.[12] No explanation for the variability of Wnt-1 mutant phenotype expressed is known, but it may be due to several factors, including genetic background.[13]

Body-Axis Formation

The role of Wnt-1 protein in body-axis formation was studied in the model organism

mRNA into early Xenopus embryo results in duplicated dorsal axis. This suggests the role of Wnt-1 as an organizer molecule and embryonic signal inducer for pattern formation.[14]

Mechanism

Wnt proteins are involved in a multitude of pathways. In most pathways, Wnt is found to interact directly with

dimerization of two CRD domains of Fzd.[16]

Canonical Beta Catenin Pathway

Wnt- Beat-Catenin Pathway

In the absence of Wnt,

axin and protein phosphatase 2A (PP2A). [15][17]This process of phosphorylation by GSK-3 β occurs at serines-33 and -37, as well as at serine-45.[18] The process is continued by β-TrCP in conjunction with ubiquitin ligase in order to mark the protein with ubiquitin for degradation. [19]

Wnt+ Beta-Catenin Pathway

A change in the cytoplasmic conformation of the proteins occurs when Wnt binds to the Fzd/LRP complex, resulting in the binding of Axin to LRP and the binding of the Dishevelled protein (Dsh) to Fzd.[20] Other transmembrane proteins found to interact with Fzd8 and assist in the signal transmission across the membrane are two low density lipoprotein receptor-related proteins, LRP5 and LRP6. [20][15]The deactivation of GSK-3β is coupled to the interaction between axin and dishevelled (DIX) domain, thus preventing the formation of the axin dependant phosphorylation complex.[21][22] This prevents phosphorylation of β-catenin and allows for its accumulation.


In the nucleus without β-catenin, two transcription factors,

Groucho, act as inhibitors of Wnt controlled genes.[17] Once build up of β-catenin occurs, it acts to from a complex with TCF/LEF. The complex then acts to induce the same genes that TCF/LEF inhibited in the absence of β-catenin, specifically those relating to cell growth and differentiation. [17]

Non Canonical Pathways

The two major non-canonical pathways are the

calcium/calmodium-dependent protein kinase II (CaMKII).[17] In developmental processes, the release of such kinases results in a decrease in the effect of the canonical beta catenin pathway, and plays a role in cell migration
and axis development. Planar Cell Polarity (PCP) is a pathway involving many of the same proteins such as Fzd and Dishevelled , but primarily plays a role in altering cell
Kinases which alter cell structure.[15] [23]

Clinical Significance

Wnt-1 mis-expression are of clinical significance since mutations are associated

chronic diseases
.

Disorder

An overexpression of Wnt-1 is correlated with tumorogenesis.

gastric cancer.[27]

Up-regulation of Wnt-1 in Medicinal Application

The

liposomes
at the sites of bone damage. This not only suggests an additional area of therapeutic research using Wnt pathways, but also the potential positive effects of up-regulated Wnt protein expressions in tissue/organ regeneration. Wnt-1 over-expression can suppress the
cardiac ischemia.[30]

Down-regulation of Wnt-1 in Medicinal Application

Inhibition studies of the Wnt-gene family were long focused due to their cancer-causing properties when over-expressed. Over-expression of Wnt-1 has demonstrated a strong causational relationship to the formation of

mammary gland tumor,[25]
a deeper understanding of the specific Wnt-1 pathway in relevant organs will potentially bring a more effective treatment therapy for breast cancer.

Conservation of Wnt-1 across Evolution

The highly conserved nature of Wnt gene throughout

model organisms, including worms, flies, and mice.[31] [2] The human Wnt-1 protein sequence is 99% identical to that of the mouse homologue.[32] Wnt-1 is usually around 350-400 amino acids in length with conserved pattern of 23-25 cysteine residues across species. [3]

Evolutionary biologists speculate the early amplification and divergence of the Wnt family were the cause for increasing complexity of animal body plans. Wnt-1 has been found conserved throughout the entire animal kingdom, often expressed in regionalized patterns.[33]


References

  1. ^ "WNT1 wingless-type MMTV integration site family, member 1 [homo sapiens]". NCBI. Retrieved 10 November 2012.
  2. ^ a b c Nusse, Roel. "The Wnt Homepage". Retrieved 10 November 2012.
  3. ^
    doi:10.1101/gad.11.24.3286 Genes & Dev. 1997. 11: 3286-3305 (inactive 2023-08-02). Retrieved 17 November 2012. {{cite journal}}: Check |doi= value (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: DOI inactive as of August 2023 (link
    )
  4. PMID [PubMed - indexed for MEDLINE 2673541 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  5. ^
    PMID 2202907. {{cite journal}}: Check date values in: |date= (help
    )
  6. PMID [PubMed - indexed for MEDLINE 20707997 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  7. ^ a b "Wnt1 protein (30R-AW002)". Fitzgerald-FII Supplier of Antibodies Protein and ELISA kits. Retrieved 18 November 2012.
  8. ^
    PMID 6297757.{{cite journal}}: CS1 maint: date and year (link
    )
  9. PMID [PubMed - indexed for MEDLINE 815114 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= and |year= / |date= mismatch (help
    )
  10. PMID [PubMed - indexed for MEDLINE 22617420 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  11. PMID 2205396. {{cite journal}}: Check date values in: |date= (help
    )
  12. PMID [PubMed - indexed for MEDLINE 1388050 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  13. PMID 1617723. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |month= ignored (help
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  14. PMID [PubMed - indexed for MEDLINE 2673541 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  15. ^
    PMID 22550232. {{cite journal}}: Check date values in: |date= (help
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  16. PMID 18505162. {{cite journal}}: Check date values in: |date= (help
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  17. ^ a b c d e f "Wnt Signaling Pathway". R and D Systems, Inc. Retrieved 18 November 2012.
  18. PMID [PubMed - indexed for MEDLINE 12417018 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  19. PMID [PubMed - indexed for MEDLINE 10339577 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  20. ^
    doi:10.1242/​jcs.02647 (inactive 2023-08-02). {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); zero width space character in |doi= at position 9 (help)CS1 maint: DOI inactive as of August 2023 (link
    )
  21. PMID 21245303. {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Unknown parameter |month= ignored (help
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  22. PMID 10428961. {{cite journal}}: Check date values in: |date= (help
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  23. ^
    PMID [PubMed - indexed for MEDLINE 21919026 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help
    )
  24. PMID [PubMed - indexed for MEDLINE 15870927 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help
    )
  25. ^
    PMID [PubMed - in process 22846569 [PubMed - in process]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  26. PMID [PubMed - indexed for MEDLINE 18790633 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  27. PMID [PubMed - indexed for MEDLINE 12469206 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  28. PMID 20427820. {{cite journal}}: Check date values in: |date= (help
    )
  29. PMID [PubMed - indexed for MEDLINE 22572818 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  30. PMID [PubMed - indexed for MEDLINE 22085926 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
  31. PMID [PubMed - indexed for MEDLINE 17310352 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
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  32. PMID 2998762. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: date and year (link
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  33. PMID [PubMed - indexed for MEDLINE 15650739 [PubMed - indexed for MEDLINE]]. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help
    )
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