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Lesson 3 Cell Signaling & Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Lesson 3 Powerpoint (click link below):

cell signaling and motility 3 finalissima sjw

Four papers to choose from for your February 11 group presentation:

Structural studies of G protein Coupled receptor

Shapiro-2009-Annals_of_the_New_York_Academy_of_Sciences

G protein as target in neurodegerative disease

fish technique

 

 

Today’s lesson 3 explains how extracellular signals are transduced (transmitted) into the cell through receptors to produce an agonist-driven event (effect).  This lesson focused on signal transduction from agonist through G proteins (GTPases), and eventually to the effectors of the signal transduction process.  Agonists such as small molecules like neurotransmitters, hormones, nitric oxide were discussed however later lectures will discuss more in detail the large growth factor signalings which occur through receptor tyrosine kinases and the Ras family of G proteins as well as mechanosignaling through Rho and Rac family of G proteins.

Transducers: The Heterotrimeric G Proteins (GTPases)

An excellent review of heterotrimeric G Proteins found in the brain is given by

Heterotrimeric G Proteins by Eric J Nestler and Ronald S Duman.

 

 

from Seven-Transmembrane receptors – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Examples-of-heterotrimeric-G-protein-effectors_tbl1_11180073 [accessed 4 Feb, 2019] and see references within

 

 

See below for the G Protein Cycle

 

 

 

 

 

 

 

 

<a href=”https://www.researchgate.net/figure/32-The-G-protein-cycle-In-the-absence-of-agonist-A-GPCRs-are-mainly-in-the-low_fig2_47933733″><img src=”https://www.researchgate.net/profile/Veli_Pekka_Jaakola/publication/47933733/figure/fig2/AS:669499451781133@1536632516635/32-The-G-protein-cycle-In-the-absence-of-agonist-A-GPCRs-are-mainly-in-the-low.ppm&#8221; alt=”.3.2: The G protein cycle. In the absence of agonist (A), GPCRs are mainly in the low affinity state (R). After agonist binding, the receptor is activated in the high affinity state (R*), and the agonist-GPCR-G protein complex is formed. GTP replaces GDP in Gα. After that the G protein dissociates into the Gα subunit and the Gβγ heterodimer, which then activate several effector proteins. The built-in GTPase activity of the Gα subunit cleaves the terminal phosphate group of GTP, and the GDP bound Gα subunit reassociates with Gβγ heterodimer. This results in the deactivation of both Gα and Gβγ. The G protein cycle returns to the basal state. RGS, regulator of G protein signalling.”/></a>

 

From Citation: Review: A. M. Preininger, H. E. Hamm, G protein signaling: Insights from new structures. Sci. STKE2004, re3 (2004)

 

For a tutorial on G Protein coupled receptors (GPCR) see

https://www.khanacademy.org/test-prep/mcat/organ-systems/biosignaling/v/g-protein-coupled-receptors

 

 

 

cyclic AMP (cAMP) signaling to the effector Protein Kinase A (PKA)

from https://courses.washington.edu/conj/gprotein/cyclicamp.htm

Cyclic AMP is an important second messenger. It forms, as shown, when the membrane enzyme adenylyl cyclase is activated (as indicated, by the alpha subunit of a G protein).

 

The cyclic AMP then goes on the activate specific proteins. Some ion channels, for example, are gated by cyclic AMP. But an especially important protein activated by cyclic AMP is protein kinase A, which goes on the phosphorylate certain cellular proteins. The scheme below shows how cyclic AMP activates protein kinase A.

Additional information on Nitric Oxide as a Cellular Signal

Nitric oxide is actually a free radical and can react with other free radicals, resulting in a very short half life (only a few seconds) and so in the body is produced locally to its site of action (i.e. in endothelial cells surrounding the vascular smooth muscle, in nerve cells). In the late 1970s, Dr. Robert Furchgott observed that acetylcholine released a substance that produced vascular relaxation, but only when the endothelium was intact. This observation opened this field of research and eventually led to his receiving a Nobel prize. Initially, Furchgott called this substance endothelium-derived relaxing factor (EDRF), but by the mid-1980s he and others identified this substance as being NO.

Nitric oxide is produced from metabolism of endogenous substances like L-arginine, catalyzed by one of three isoforms of nitric oxide synthase (for link to a good article see here) or release from exogenous compounds like drugs used to treat angina pectoris like amyl nitrate or drugs used for hypertension such as sodium nitroprusside.

The following articles are a great reference to the chemistry, and physiological and pathological Roles of Nitric Oxide:

46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

47. Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

Biochemistry of the Coagulation Cascade and Platelet Aggregation: Nitric Oxide: Platelets, Circulatory Disorders, and Coagulation Effects

Nitric Oxide Function in Coagulation – Part II

Nitric oxide is implicated in many pathologic processes as well.  Nitric oxide post translational modifications have been attributed to nitric oxide’s role in pathology however, although the general mechanism by which nitric oxide exerts its physiological effects is by stimulation of soluble guanylate cyclase to produce cGMP, these post translational modifications can act as a cellular signal as well.  For more information of NO pathologic effects and how NO induced post translational modifications can act as a cellular signal see the following:

Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?

58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.

https://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

Note:  A more comprehensive ebook on Nitric Oxide and Disease Perspectives is found at

Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

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Lesson 1 & 2 Cell Signaling & Motility: Lessons, Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

UPDATED 2/05/2019

Syllabus for Cell Signaling & Motility for 2019

CELL SIGNALING AND MOTILITY (BIOL 3373)

SPRING 2017

Lectures:

Monday 5:00 PM – 8:00 PM

Biology Life Sciences, Room 342

Instructor:

Antonio Giordano, M.D., Ph.D.

Office hours: Biology Life Sciences Building, Room 431.

Friday: 12:00 noon – 2:00 PM. By appointment

(Phone: 215-2049520, or email: giordano@temple.edu).

Prerequisite:

BIO 3096, Cell Structure and Function (Minimum Grade of C- | May not be taken concurrently). 

Description:

The communication among cells is essential for the regulation of the development of an organism and for the control of its physiology and homeostasis. Aberrant cellular signaling events are often associated with human pathological conditions, such as cancer, neurological disorders, cardiovascular diseases and so on. The full characterization of cell signaling systems may provide useful insights into the pathogenesis of several human maladies.

Text:

Molecular Biology of the Cell 6th Edition, Alberts et al. Garland Science. This textbook is available at the Temple Bookstore.

Grading:

The final grade will be based on the score of four examinations that include both group and individuals assignment. Each exam accounts for 25% of the final grade. There will be no make-up tests during the course. If you have a documented medical excuse and you contact me as soon as possible after the emergency, I will arrange a make-up exam. Complaints regarding the grading will not be considered later than two weeks after the test is returned.

Blackboard:

Announcements will be readily posted on Blackboard. It is your responsibility to check Blackboard periodically.

Attendance: Lecture attendance is mandatory. In addition, punctuality is expected.

Disabilities: Students with documented disabilities who need particular accommodation should contact me privately as soon as possible.

Honesty and Civility:

Students must follow the Temple’s Code of Conduct (see http://www.temple.edu/assistance/udc/coc.htm). This Code of Conduct prohibits: 1. Academic dishonesty and impropriety, including plagiarism and cheating. 2. Interfering or attempting to interfere with or disrupting the conduct of classes or any other activity of the University.”

Academic Rights and Responsibilities:

The policy of the University that regulates Student and Faculty Academic Rights and Responsibilities (Policy # 03.70.02) is available at the following web link: http://policies.temple.edu/getdoc.asp?policy_no=03.70.02

This policy sets the parameters for freedom to learn and freedom to teach, which constitute the pillars of academia.

 

SCHEDULE

This schedule is a general outline, which may be eventually modified. Changes will be announced in advance. Please, always check Blackboard and your email.

Date Topic
Jan 14 Introduction (course overview  and discussion of syllabus). General concepts: Eukaryotic and prokaryotic cell; DNA, RNA  and proteins: Protein synthesis
Jan 21 Martin Luther King, Jr. Day (no classes held)
Jan 28 DNA analysis, RNA analysis; Proteins analysis; Microscopy.
Feb 4 Signaling: general concepts; Introduction to G-proteins; signaling via G-proteins (1)
Feb 11 Exam 1: In class presentation (group assignment)
Feb 18 Signaling via G-proteins (2); tyrosine kinase receptors signaling; Ras-MAPK pathway.
Feb 25 Exam 2: In class presentation (group assignment)
March 4- 10 Spring break
Mar 11

 

Cytoskeleton:  Intermediate filaments; actin
Mar 18 Cytoskeleton: actin binding proteins; microtubules
Mar 25

 

Cytoskeleton: microtubules
April 1

 

Exam 3: in class Multiple choice questions (individual assignment)
Apr 8 Extracellular matrix; cell adhesion; coordinated polarization.
Apr  15 Cell motility and Wnt Signal Signaling. 
Apr  22 Medical consequences of aberrant signaling pathways; production of small molecules for protein kinases In cancer therapy.
Study days
May 6 Exam 4: In class presentation (group assignment)

 

Below is Powerpoint presentations for Lesson 1 and Lesson 2.  Please check for UPDATES on this page for additional supplemental information for these Lessons including articles from this Online Access Journal

 

cell signaling and motility 1 lesson

 

cell signaling and motility 2 lesson

The following articles and curations discuss about the new paradigm how we now envision DNA, in particular how we now understand that the important parts of the genome are not just the exons which code for proteins but also the intronic DNA, which contains all the regulatory elements such as promoters, lnDNA, miRNA sequences etc.  These are good reads for your presentations.

The Search for the Genetic Code

Junk DNA codes for valuable miRNAs

 

And on How the Cell Creates Diversity post the Genetic Code by Use of Post Translational Modifications to Bring Diversity to Protein Structure/Function

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Also there is a link to a Blood article using FISH to detect gene amplifications after Gleevec resistance onset here

Novel Mechanisms of Resistance to Novel Agents

Other Articles related to the #TUBiol3373 course include:

Lesson 9 Cell Signaling: Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBioll3373

Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

 

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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD 

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases.  This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof.  However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.

From:

Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP

 

Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca2+ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca2+ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca2+ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca2+ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca2+ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.

 

 

 

In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor).  It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD.  Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function.  Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).

 

In Cardiovascular and Thrombotic Disease

 

Adenosine Receptor Agonist Increases Plasma Homocysteine

 

and read related articles in curation on effects of hormones on the cardiovascular system at

Action of Hormones on the Circulation

 

In Cancer

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

 

Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.

 

 

 

 

 

 

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Lesson 9 Cell Signaling:  Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBiol3373

Stephen J. Wiilliams, Ph.D: Curator

The following contain curations of scientific articles from the site https://pharmaceuticalintelligence.com  intended as additional reference material  to supplement material presented in the lecture.

Wnts are a family of lipid-modified secreted glycoproteins which are involved in:

Normal physiological processes including

A. Development:

– Osteogenesis and adipogenesis (Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes)

  – embryogenesis including body axis patterning, cell fate specification, cell proliferation and cell migration

B. tissue regeneration in adult tissue

read: Wnt signaling in the intestinal epithelium: from endoderm to cancer

And in pathologic processes such as oncogenesis (refer to Wnt/β-catenin Signaling [7.10]) and to your Powerpoint presentation

 

The curation Wnt/β-catenin Signaling is a comprehensive review of canonical and noncanonical Wnt signaling pathways

 

To review:

 

 

 

 

 

 

 

 

 

 

 

Activating the canonical Wnt pathway frees B-catenin from the degradation complex, resulting in B-catenin translocating to the nucleus and resultant transcription of B-catenin/TCF/LEF target genes.

Fig. 1 Canonical Wnt/FZD signaling pathway. (A) In the absence of Wnt signaling, soluble β-catenin is phosphorylated by a degradation complex consisting of the kinases GSK3β and CK1α and the scaffolding proteins APC and Axin1. Phosphorylated β-catenin is targeted for proteasomal degradation after ubiquitination by the SCF protein complex. In the nucleus and in the absence of β-catenin, TCF/LEF transcription factor activity is repressed by TLE-1; (B) activation of the canonical Wnt/FZD signaling leads to phosphorylation of Dvl/Dsh, which in turn recruits Axin1 and GSK3β adjacent to the plasma membrane, thus preventing the formation of the degradation complex. As a result, β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it promotes the expression of target genes via interaction with TCF/LEF transcription factors and other proteins such as CBP, Bcl9, and Pygo.

NOTE: In the canonical signaling, the Wnt signal is transmitted via the Frizzled/LRP5/6 activated receptor to INACTIVATE the degradation complex thus allowing free B-catenin to act as the ultimate transducer of the signal.

Remember, as we discussed, the most frequent cancer-related mutations of WNT pathway constituents is in APC.

This shows how important the degradation complex is in controlling canonical WNT signaling.

Other cell signaling systems are controlled by protein degradation:

A.  The Forkhead family of transcription factors

Read: Regulation of FoxO protein stability via ubiquitination and proteasome degradation

B. Tumor necrosis factor α/NF κB signaling

Read: NF-κB, the first quarter-century: remarkable progress and outstanding questions

1.            Question: In cell involving G-proteins, the signal can be terminated by desensitization mechanisms.  How is both the canonical and noncanonical Wnt signal eventually terminated/desensitized?

We also discussed the noncanonical Wnt signaling pathway (independent of B-catenin induced transcriptional activity).  Note that the canonical and noncanonical involve different transducers of the signal.

Noncanonical WNT Signaling

Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP3/DAG/Ca++ and/or kinases such as MAPK, JNK.

Depending on the different combinations of WNT ligands and the receptors, WNT signaling activates several different intracellular pathways  (i.e. canonical versus noncanonical)

 

In addition different Wnt ligands are expressed at different times (temporally) and different cell types in development and in the process of oncogenesis. 

The following paper on Wnt signaling in ovarian oncogenesis shows how certain Wnt ligands are expressed in normal epithelial cells but the Wnt expression pattern changes upon transformation and ovarian oncogenesis. In addition, differential expression of canonical versus noncanonical WNT ligands occur during the process of oncogenesis (for example below the authors describe the noncanonical WNT5a is expressed in normal ovarian  epithelia yet WNT5a expression in ovarian cancer is lower than the underlying normal epithelium. However the canonical WNT10a, overexpressed in ovarian cancer cells, serves as an oncogene, promoting oncogenesis and tumor growth.

Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence

Benjamin G. Bitler,1 Jasmine P. Nicodemus,1 Hua Li,1 Qi Cai,2 Hong Wu,3 Xiang Hua,4 Tianyu Li,5 Michael J. Birrer,6Andrew K. Godwin,7 Paul Cairns,8 and Rugang Zhang1,*

A.           Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the US. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a non-canonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We demonstrate that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; p = 0.039) or fallopian tube epithelium (n = 28; p < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (p = 0.003) and predicts shorter overall survival in EOC patients (p = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A (HIRA)/promyelocytic leukemia (PML) senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.

Oncol Lett. 2017 Dec;14(6):6611-6617. doi: 10.3892/ol.2017.7062. Epub 2017 Sep 26.

Clinical significance and biological role of Wnt10a in ovarian cancer. 

Li P1Liu W1Xu Q1Wang C1.

Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of β-catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK-974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/β-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/β-catenin signaling pathway.

Targeting the Wnt Pathway includes curations of articles related to the clinical development of Wnt signaling inhibitors as a therapeutic target in various cancers including hepatocellular carcinoma, colon, breast and potentially ovarian cancer.

 

2.         Question: Given that different Wnt ligands and receptors activate different signaling pathways, AND  WNT ligands  can be deferentially and temporally expressed  in various tumor types and the process of oncogenesis, how would you approach a personalized therapy targeting the WNT signaling pathway?

3.         Question: What are the potential mechanisms of either intrinsic or acquired resistance to Wnt ligand antagonists being developed?

 

Other related articles published in this Open Access Online Scientific Journal include the following:

Targeting the Wnt Pathway [7.11]

Wnt/β-catenin Signaling [7.10]

Cancer Signaling Pathways and Tumor Progression: Images of Biological Processes in the Voice of a Pathologist Cancer Expert

e-Scientific Publishing: The Competitive Advantage of a Powerhouse for Curation of Scientific Findings and Methodology Development for e-Scientific Publishing – LPBI Group, A Case in Point 

Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

 

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