TNF Pathway

The TNF pathway is very important in the sense that it plays a role both in cell proliferation and apoptosis. When it comes to cell proliferation, the molecule NFκB is termed as the major player. The pathway functions as follows. When TNF comes and binds to the TNF receptor, the receptor summons a molecule called TRAF. As soon as TRAF gets attached, a series of processes take place most importantly the poly-ubiquitination of TRAF itself. This process in turn stimulates the phosphorylation of IKK (IκB kinases). These kinases inturn inhibit the IκB domains thereby releasing NFκB. This molecule brings about cell proliferation.

Ras/MAPK pathway

The Ras/MAPK pathway is very important as it plays a role in cell proliferation, cell differentiation and also cell migration. The molecule Ras plays an important role in activating the MAPK pathway. Initially, it is in an inactive state being associated with GDP molecules. When the mitogenic signals (TGF alpha) come and bind to the Tyrosine Kinase receptors, it results in the activation of Ras. This results in the activation of the MAPK Pathway. The MAPK pathway in turn activates the cyclin molecule which associates with the CDK molecules present in the cell. This interaction results in the formation of the Cyclin-CDK complex. This complex then interacts with a protein P^Rb. The function of P^Rb is to bind with the E2F Transcription factor and inhibit it. But the cyclin-CDK complex phosphorylates P^Rb thereby preventing its interaction with E2F. This results in cell proliferation.

UNDERSTAND CANCER website.

Dear Readers,

This is to inform you that the Understand Cancer website is up with all the network trees. Each Cell Behavior is expressed by a number of Cell Processes namely:

(a) Signal Generation
(b) Signal Transmission
(c) Signal Sensing
(d) Signal Transduction
(e) Transcription

We are in the process of developing rules for the model at this moment.

Sidharth Mohandas
Understand Cancer
understandcancer@aol.com

Vegetables!!!

Majority of the questions I receive related to cancer is as to what diet we should follow so as to protect from cancer. Though I hate saying this the answer is obvious: Vegetables! Research has identified many ingredients in vegetables that can protect from different types of cancers.

Vegetables with the Highest Anti-cancer Activity

• garlic
• cabbage
• soy
• ginger
• umbelliferous vegetables such as carrots, celery, cilantro, parsley and parsnip

Vegetables with the Modest Anti-cancer Activity

• onions
• flax seed
• citrus
• cruciferous vegetables such as broccoli, Brussels sprouts and cauliflower
• solanaceous vegetables such as tomato (rich in lycopene) and peppers

Gums for Cancer

Hey guys, guess what…they developed chewing gums to prevent cancer! We know that over 80% of mouth and throat cancers are linked to smoking and drinking- as smoking and drinking increases the acetaldehyde level in our body- which is linked to a greater risk of cancer. However the amino acid, L-cysteine , can bind effectively to acetaldehyde and block it from causing cancer. From these facts, the University of Helsinki developed a tablet containing L-cysteine.

Apoptosis and Cancer

Figure 1: TNF R, TRADD and apoptosis

Figure 2: Apoptosome formation and apoptosis

n

n

• The transcription factor E2F 1 plays a very important role in all the aspects related to cancer making it one of the most important component in the cancer cycle.

• Apoptosis pathways are of two types viz.

1. Death receptor pathway (DR)
2. Mitochondrial pathway (M)
   

• The DR pathway involves the FAS and TNF pathway. FAS receptor interacts with both FADD and DAXX to activate caspases. These caspases bring about apoptosis
  
  
• Whereas, TNF receptor interacts with TRADD and activates caspases.
  
  
• E2F also plays a role in apoptosis by downregulating TRAF 2 which is responsible for NFKB activation.
  
  
• The M pathway involves a lot of factors. First in response to a stress signal, mitochondria releases cytochrome C.
  
  
• E2F 1 activates a protein called APAF 1. Cytochrome C and APAF 1 form a complex called Apoptosome.
  
  
• The apoptosome will go and activate the effector caspases and it will bring about apoptosis.

[Courtesy to R. Sitaram, cancerousapproach.blogspot.com]

MSG and Cancer

Monosodium Glutamate [MSG] is causing great concern in the medical community because it stimulates brain cell activity. MSG tricks your brain to think the food you are eating tastes good. Manufacturers can use inferior ingredients and thus make a product seem tastier than the reality. Contrary to what society believes, MSG intolerance is not an allergic reaction but a drug reaction that destroy brain cells.

Two recent studies from the Salk Institute show us that, MSG is twelve times larger than its simplified IUPAC chemical ratio formula. They also showed that the reason MSG tends to create malignant cysts is because MSG replaces the glutamic acid in the protein strands in persons deficient in glutamic acid. As said before, when the glutamate level increases, cancer just grows like wildfire.

Laugh!

EXCITOTOXINS

Excitotoxins have been found to dramatically promote cancer growth and metastasis. In fact, one aspartame researcher noticed that, when cancer cells were exposed to aspartame, they became more mobile, and you see the same effect with MSG. It also causes a cancer cell to become more mobile, and that enhances metastasis, or spread. These MSG-exposed cancer cells developed all of these pseudopodians and started moving through tissues, which is one of the earlier observations from cancer.

When you increase the glutamate level, cancer just grows like wildfire, and then when you block glutamate, it dramatically slows the growth of the cancer. Researchers have done some experiments in which they looked at using glutamate blockers in combination with conventional drugs, like chemotherapy, and it worked very well. It significantly enhanced the effectiveness of these cancer drugs.

[to be continued w.r.t MSG]

Cancer Bug

Figure taken from AAS

Helicobacter pylori, or H. pylori, is a spiral-shaped bacterium that is able to grow in the human stomach. Normally, the acidic stomach environment prevents the survival of viruses, bacteria, and other microorganisms. However, H. pylori has evolved to be uniquely suited to thrive in the harsh stomach environment. H. pylori bacteria secrete urease, a special enzyme that converts urea to ammonia. Ammonia reduces the acidity of the stomach, making it a more hospitable home for H. pylori.

Research has shown that bacterial toxins released by H. pylori and the inflammation that results from infection can damage the stomach lining and cause peptic ulcers. Although statistics vary depending on geographical region, H. pylori is responsible for the large majority of peptic ulcers. These ulcers can eventually lead to cancer.

Stomach cancer and Lymphoma are two types of cancer related to H. pylori. This does not mean that all people with H. pylori infection will develop cancer; in fact, very few do. However, it is likely that if the infection is present for a long time, perhaps from childhood, these cancers may then develop. This is another reason why it is important to treat H. pylori infection.

Pesticides and Cancer

By Gwen Petreman
http://www.livinggreen.info/library/pestices_and_cancer.cfm

The most convincing evidence that pesticides are carcinogens comes from epidemiological studies. Farmers who frequently use 2,4-D have a six-fold increase in non-Hodgkin’s lymphoma. Scientists believe that the use of lawn chemicals such as 2,4-D has been a significant factor in the 50% rise in non-Hodgkin’s lymphoma over the past 20 years in the American population. (World health Organization. 2,4-D Environmental Aspects. Geneva, Switzerland, 1989.) 2,4-D has also been linked to malignant lymphoma in dogs. Pets are exposed to higher doses of pesticides because they are closer to the ground where concentrations are the highest. Parts of their bodies, such as their scrotum and armpits, are often directly exposed to pesticides. They also ingest pesticides when they are grooming themselves. Studies show that the risk of lymphomas doubled in dogs whose owners treated lawns four times a year.

The lawn pesticides, mancozeb and chlorothalonil have been classified by the EPA as "probable" cancer causing chemicals in humans, as they have been found to cause cancer in animals. Mancozeb has also been found to react with sunlight to form a new compound the EPA categorizes as a "known" human carcinogen. The common lawn pesticide 2,4-D has been shown to increase the risk of lymphatic cancer in farmers six times the normal rate, according to a National Cancer Institute report. (Sinclair, W. 18 Studies Show Why Pesticides Are More Dangerous than Previously Realized. Tampa, Florida)

A University of Iowa study found that working as a golf superintendent significantly increased one’s risk of getting non-Hodgkin’s lymphoma, brain cancer, lung cancer, large intestine cancer, and prostrate cancer. Other experts are starting to find that golfers, and non-golfers who live near golf courses, are experiencing similar health problems. A 1996 research project studied brain cancer rates among 600 people. The research demonstrated a twofold increase risk for developing brain cancer for people who lived within 2600 feet of an agricultural area. (American Journal of Public Health, 86(9): 1289-96, 1996.) In 1983 the National Cancer Institute studied 3,827 Florida pesticide applicators who had been spraying for more than 20 years. They found that these pesticide applicators had nearly 3 times the risk of developing lung cancer and 2 times the risk of developing brain cancer. There was no increased risk for pesticide applicators who had been spraying for only 5 years. (Journal of the National Cancer Institute, 71(1), July 1983.)

Beginning in the late 1970s there have been reports linking pesticides to leukemia in children. A 1987 study by the National Cancer Institute showed that children living in pesticide-treated homes had nearly a 4 times greater risk of developing leukemia (cancer of the blood). If the children lived in homes where pesticide was sprayed on lawns and gardens, the risk of developing leukemia was 6.5 times greater. All the children in the study were 10 years of age or younger. (Dr. John Peters, University of Southern California, Journal of the National Cancer Institute, July 1987.) Cancer rates in the US have increased by 37% between 1950 and 1986. Over a million people are diagnosed with cancer in the US reach year. 10,400 people in the US die each year from cancer related to pesticides. It is estimated that the cost of cancer in term of lost production, income, and medical expenses amount to over US $38 billion each year.

Artificial sweeteners and Cancer

Is there an association between artificial sweeteners and cancer?

Questions about artificial sweeteners and cancer arose when early studies showed that cyclamate in combination with saccharin [In figure] caused bladder cancer in laboratory animals. However, results from subsequent carcinogenicity studies (studies
that examine whether a substance can cause cancer) on these sweeteners and other approved sweeteners have not provided clear evidence of an association between artificial sweeteners and cancer in people.

[Taken from NCI]

Telomerase Activation

Li-Fraumeni's Syndrome

"We have known since 1990 that Li-Fraumeni was associated with inheritance of a mutated form of the p53 tumor suppressor gene, but we also noticed each generation developed cancer earlier than the preceding generation," said David Malkin, M.D

"We were able to look at the DNA of multiple members of families that carried Li-Fraumeni and, overwhelmingly, telomere length was shorter in children with cancer than in unaffected siblings or parents," Malkin said. "Children whose telomeres were shorter than their parents who had the disease typically began developing cancer at a much earlier age than their parents."

Telomeres are repeated sequences of DNA at the tips of every chromosome that function as a sort of genetic slack. As cells grow and divide throughout life, the chromosomes, which contain all of an individual's genetic information, replicate as well. The enzymes that create copies of chromosomes cannot, however, physically reach the very end of the chromosome, so they leave a minute bit of this telomere slack behind each time. This is known to researchers as the "end replication problem" and has made telomeres an important subject of research in the science of aging and cancer. While Malkin and his colleagues link telomeres to genetic instability and cancer in the context of Li-Fraumeni syndrome, other researchers have studied whether it might be possible to kill rapidly growing tumors by accelerating telomere attrition.

What is chemobrain?

The terms "chemobrain" and "chemofog" refer to cognitive changes during and after cancer diagnosis and treatment. Though these terms imply a relation to chemotherapy, it isn't clear that chemotherapy is responsible. Women with breast cancer who underwent chemotherapy were the first group to bring these symptoms to light, as more started mentioning their symptoms to their doctors. It isn't clear whether chemotherapy, or other factors such as stress and hormonal fluctuations, cause the changes in memory and thinking. What is clear is that some people with cancer do notice increased difficulties with certain mental tasks during and after cancer treatment.

In general, researchers have found that chemotherapy can affect your cognitive abilities in the following ways:

• Word finding. You might find yourself reaching for the right word in conversation.
• Memory. You might experience short-term memory lapses, such as not remembering where you put your keys or what you were supposed to buy at the store.
• Multitasking. Many jobs require you to manage multiple tasks during the day. Multitasking is important at work as well as at home — for example, talking with your kids and making dinner at the same time. Chemotherapy may affect how well you're able to perform multiple tasks at once.
• Learning. It might take longer to learn new things. For example, you might find you need to read paragraphs over a few times before you get the meaning.
• Processing speed. It might take you longer to do tasks that were once quick and easy for you.

[Taken from Mayoclinic.com]

Exhaust Cancer

When there is something wrong with the fruit, the best approach is to go to the root. And that's exactly what we're trying to do here at RRL. Getting to the molecular level and finding out which signaling pathways and molecular interactions are responsible for the formation and development of cancer. If you would have noticed in the pathway explanations I have put up in this blog: activation of small signaling pathways is what leads to such a dreadful disease. So what we need is a complete database of molecular interactions that will lead to cancer- either by activation of cell proliferation or by inhibition of apoptosis, which ever way it is. This is what we call the systems biological approach to cancer. With such a big database as our source, we can try all given possibilities that can lead to cancer on a computational model. The alteration of which molecule in a normal cell signaling pathway leads them to be cancerous? The activation of which extra cellular molecule will trigger the activation of a cascade that will promote cancer? Can we make drugs that can target more than one signaling pathways?

When we fight cancer, we need to exhaust all it's approaches to attack us.

Declaring war against cancer,
Sidharth Mohandas

Common Cold Virus kills Cancer

Australian studies have found the Coxsackie Cold virus can kill cancer cells in a test tube and in mice but leaves normal tissue largely unaffected.

Biomedical scientist Kathryn Skelding, of the University of Newcastle, said if the treatment proved successful, the hope was that it may eventually replace chemotherapy and radiation, which both have debilitating side effects for patients, including nausea and hair loss.

Article on Wikipedia

Article on Neuromedin B posted by Sidharth Mohandas on Wikipedia

More about Aromasin

Exemestane is a medicine that is used to treat breast cancer in women whose disease has progressed while they were taking tamoxifen.

Many breast cancer tumors grow in response to estrogen. Exemestane interferes with the production of estrogen in the body. As a result, the amount of estrogen that the tumor is exposed to is reduced, limiting the growth of the tumor. This medicine is meant to be used only by women who have already stopped menstruating.

Before you begin treatment with exemestane, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

Aromasin Beats Tamoxifen

[ Source: Xinhuanet ]

The new drug exemestane for breast cancer treatment could improve survival rates by 17 percent, new research shows.

A study of 4,742 post-menopausal women found that switching from the present gold-standard breast cancer treatment Tamoxifen to the new drug Exemestane after two or three years resulted in a dramatic fall in death rates, The Times newspaper reported on Tuesday.

The new drug, sold under the brand name Aromasin, is recommended by the National Institute for Health and Clinical Excellence as an alternative to tamoxifen after two to three years, according to the report.

The study followed the progress of women treated for a total of five years and monitored for a further three years, and women assigned randomly to a full five years of tamoxifen, or treatment with tamoxifen followed by exemestane.

The researchers said that giving women tamoxifen after surgery already reduced the risk of dying by 33 percent, and after another two to three years of exemestane, and with a further three years of post-treatment follow-up, survival was found to be significantly improved with the risk of dying 50 percent lower than if they had received no drug therapy.

"This is the first time any hormone treatment has been shown to reduce the death rate more than tamoxifen alone. Switching drugs also seems to avoid the side-effects of long-term tamoxifen therapy, such as cancer of the womb and deep vein thrombosis," Charles Coombes, director of the Cancer Research UK Laboratories and head of cancer medicine at Imperial College, London, was quoted as saying.

The charity Cancer Research UK, whose scientists were involved in the study, said that the treatment would prevent an estimated 1,300 annual deaths in this country.

Calcium Conscious

Here’s a call to be diet conscious!

Many years back, the Harvard University found out that excess of Calcium in diet can lead to Prostrate Cancer. The explanation that most hold onto is that calcium can reduce the Vitamin D level in our body, which protects the prostrate gland. It has also been noted that Vitamin D can slow down the growth of cells, which in turn will prevent the progression of cancer.

DOGS CAN SMELL CANCER

I'm sure this one will amaze you: New studies show that dogs can detect cancer by just sniffing the breath of the person. Ordinary household dogs with only a few weeks of basic "puppy training" learned to accurately distinguish between breath samples of lung- and breast-cancer patients and healthy subjects.

[Taken from National Geographic News]

Dogs can identify chemical traces in the range of parts per trillion. Previous studies have confirmed the ability of trained dogs to detect skin-cancer melanomas by sniffing skin lesions.

Also, some researchers hope to prove dogs can detect prostate cancer by smelling patients' urine.

"Canine scent detection of cancer was something that was anecdotally discussed for decades, but we felt it was appropriate to design a rigorous study that seriously investigated this topic to better evaluate its effectiveness," said Nicholas Broffman, executive director of the Pine Street Foundation.

Lung- and breast-cancer patients are known to exhale patterns of biochemical markers in their breath.

"Cancer cells emit different metabolic waste products than normal cells," Broffman said. "The differences between these metabolic products are so great that they can be detected by a dog's keen sense of smell, even in the early stages of disease."

Green Tea and Cancer

Green tea contains anti-oxidant which may have a protective effect against cancer. However, now they have found out that there are chemicals in green tea that can shut down a key molecule that plays a significant role in cancer development. Recently a team of researchers found out that the polyphenols present in Green tea reduced the IGF-1 [Insulin-like Growth Factor- mentioned in the article "Surivival Factors"]. Increased level of IGF-1 are associated with higher risk of several cancers such as prostrate, breast, lung and colon cancer.

POKEMON AND CANCER

In January 2005, the Scientists at MSKCC identified a new cellular oncogene that was essential for cancer development. The investigators named this oncogene as Zbtb7, formerly called Pokemon [POK Erythroid Myeloid ONtogenic factor]. Unlike other oncogenes, Zbtb7 is required for the activation of other oncogenes to cause cancer. The Zbtb7 protein plays such a crucial role in cancer formation, that in future we could develop drugs targeting this protein.

In their experiment on mice, when the researchers "knocked out" the Zbtb7 gene, they found out that the cells were no longer turning cancerous. Zbtb7 represses the function of a number of proteins like the tumor suppressor ARF [ARF normally binds with MDM-2 and thus blocks MDM-2 from binding to p53, thereby activatinng p53].

INTEGRIN SIGNALING

• Integrins are heterodimeric receptors of non-covalently linked α and β subunits.
  
  
• Most integrins function as receptors of ECM proteins, however some family members such as β₂ integrins, α ₄ β ₁ integrins mediate heterotypic cell-cell adhesion.
  
  
• Integrins interact with ECM and mediates intracellular signals in response to the ECM.
  
  
• Integrin couples the ligand on the ECM outside the cell to the Cytoskeleton inside the cell.
  
  
• Which ligand in the ECM the Integrin binds to depends on which α and β subunits the integrin is made of.
  
  
• Examples of ECM ligands: Fibronectin, Vitronectin, Collagen, Laminin.
  
  
• The connection between the Integrins and the ECM ligands, and the microfilament [cytoskeleton] are linked via proteins like TALIN, PAXILLIN, and α-ACTININ.
  
  
• The binding of the ECM ligand to the Integrin, leads to the assembly of Focal Adhesion Plaque [FAP]- a complex of cytoskeleton proteins and signaling molecules including, Paxillin, Talin, Viscullin, Tensin, α- Actinin and FAK [Focal Adhesion Kinase].
  
  
• This process of formation of FAP is dependent on GTPase Rho A
  
  
• The linker proteins such as talin, paxillin and alpha-actinin leads to the activation of the FAK. Figure: Integrin signaling pathway
  
  

• The FAK phosphorylates substrates such as p130CAS [CAS], thereby recruiting signal adaptors such as Crk. Crk in turn activates JNK [c-Jun NH₂ amino terminal kinase]. JNK, upon activation enters the nucleus and activates c-Jun transcription factor and ATF-2 [Activation Transcription Factor- 2]. Thus regulating the AP-1-dependent transcription. [Note: AP-1[Activator Protein] Transcription factor is a heterodimer of c-Jun and c-Fos. This AP-1 binds to the DNA via leucine zippers and promotes cell proliferation.]

SURVIVAL FACTORS

• It was discovered that a well known survival factor IGF-1 [Insulin like Growth Factor-1] works by sabotaging a component of death machinery.

• It was found that IGF-1 specifically dispatches a pair of messengers that help to sequester the notorious death factor BAD. And thus preventing it from killing the cells.

• IGF-1 is peptide molecule that is similar to the structure of Insulin.

• It has 70 amino acids and is produced by the Liver as an endocrine hormone.

• IGF-1 acts by binding to specific IGF receptors [Tyrosine Kinase Receptor] leading to a series of intracellular events.

• IGF-1 is the most potent natural activator of Akt pathway. When IGF-1 binds to it's receptor, it activates PI-3K [Phosphoinositide 3-kinases].

• PI-3K in turn phosphorylate Ptdlns(4,5)P₂ to Ptdlns(3,4,5)P₃ [PIP₂ to PIP₃]

• The conversion of PIP₂ to PIP₃ causes PDK-1[Phosphoinositide Dependent Kinase-1] to come in contact with Akt.

• PTEN acts as phosphatase to dephosphorylate PIP₃ to PIP₂.
  
  Figure: Activation by IGF-1

• Now once Akt is activated it regulates the expression of many factors. Some of them will be mentioned below:

1. BAD: The pro-apoptotic protein of the BCl-2 family is phosphorylated at Ser136, thus causing BAD to dissociate from the BCl-2 complex and it loses it's pro-apoptotic functions.
   
   
2. NF-KB [Nuclear Factor Kappa B] is the primary Transcription Factor in all cell types. Incorrect regulation of NF-KB can lead to cancer. In unstimulated cells NF-KB dimers are sequestered in the cytoplasm by a family of inhibitors called of IKB [Inhibitor of Kappa B], which are characterized by proteins of multiple Ankyrin repeats. By virtue of these Ankyrin repeats the IKB can mask NF-KB. However, when Akt is activted, it in turn activates IKK [IKB Kinase]. IKK is an enzyme that can inhibit the action of IKB, and thus rescues NF-KB from it's hands. This NF-KB is now free to enter into the nucleus and it activates transcription of variety of anti-apoptotic genes such as the c-IAP 1 and 2 [Inhibitor of Apoptosis]
   
   
3. MDM-2 - murine double minute- 2 is also activated by Akt, which in turn inhibits the tumor suppressor p53.
   
   
4. FH [FKHRL-1] is a protein that turns another death gene. Akt inhibits FH and thus prevent apoptosis.
   

• PI-3K converts PIP₂ to PIP₃ and DAG. When PIP₃ is received by the PIP₃ receptor, it causes the release of Calcium. DAG and calcium together are required for the activation of an enzyme called conventional or c-Protein Kinase C [PKC]. DAG and Ca²⁺ activates the conventional PKC.
  
  
• While only DAG is required for the activation of n-PKC or novel Protein Kinase C isoforms, i.e. PKC δ, ε, η, µ and θ.
  
  
• And PIP₃ alone is involved in the activation of Atypical isoforms of PKC, i.e. PKC λ and ζ.
  
  
• The PKC's thus formed in turn activates NF-KB, followed by the transcription of anti-apoptotic genes.

Estrogen and Cell Proliferation

Estrogen

• Estrogen is a steroid hormone produced by the ovaries.
• Estrogen is also produced in small quantities in the liver, adrenal glands and the breasts.
• They are produced more in women and than in men.
• In women they promote the development of secondary sexual characters such as breasts, thickening of endomterium [wall of the uterus] etc.
• In men they are required for the maturation of sperms.
• Around 80% of breast cancers require estrogen for it's growth. Such cancers are known as hormone-sensitive cancers. Therefore, suppression of production of estrogen in the body can be used for treating such cancers.
  

Mechanism: Figure: Eestrogen signaling pathway

• Since Estrogen is a steroidal hormone, it can pass through phospholipid cell membranes of the cell.
• This estrogen goes and binds with the estrogen receptor [ER] present within in the nucleus called generally as the Nuclear Hormone Receptors [NHR]. This complex of estrogen and it's receptor binds to the Estrogen Response Element [ERE]. This in turn activates transcription of ERE.
  
  
• There are two hypothesis to explain the relationship of estrogen and cancer:

1. Binding of Estrogen to ER causes proliferation of mammalian cells, the resulting increase in cell division and DNA replication leads to mutation- leading to the disruption of apoptosis and DNA repair and thus to tumor growth.
2. Estrogen metabolism results in the production of genotoxic wastes that in turn causes tumor growth.

Neuromedin B

• Neuromedin B is a Bombesin-related peptide in mammals.

• It was originally purified from pig spinal cord, and later shown to be present in human CNS [Central Nervous System] and GIT [Gastro-Intestinal Tracts]

• It has many functions:
  1. Regulation of exocrine and endocrine secretions
  2. Regulation of blood pressure and glucose level
  3. Regulation of body temperature
  4. Regulation of CELL GROWTH.
  
  Figure 1: NMB, 7-TMR receptor and G-protein
  
  Figure 2 : Signal Cascade after NMB binding

• NMB exerts it's effects by binding to the cell surface receptor.

• A high affinity receptor called NMB receptor [NMBR] has been identified. This receptor is a GPCR [G-Protein Coupled Receptor] with seven transmembrane spanning regions, hence the receptor is also denoted as 7-TMR or 7 Transmembrane Receptor [Shown in Figure 1].

• Upon binding several intracellular signaling cascades are induced, which are mentioned below. [Refer Figure 2 for Signal cascade]

• When NMB binds to 7-TMR, the Heterotrimeric G-protein that is attached to the receptor gets activated.

• The G-protein is called Heterotrimeric because it consists of 3 polypeptides: α subunit, β subunit and γ subunit. Out of which G-β and G-γ subunits function as a monomer. And G-α has a GDP bound to it. When the NMB binds to 7-TMR, there occurs GTP exchange for GDP bound to G-α subunit and thus it gets activated, dissociates from the G-βγ.

• The activated G-α in turn activates Adenylyl Cyclase[AC] which in turn catalyzes the conversion of ATP to cAMP [second messenger].

• cAMP helps in the activation of the enzyme PKA or Protein Kinase A.

• PKA enters the nucleus and activates the CREB [cAMP Response Element-Binding] protein

• The activated CREB binds along with CBP [CREB Binding Protein, co-activator] to the CRE region of the DNA in the nucleus. [CREB and CBP are held together by leucine zippers]

• CRE is the control that activates number of growth factors, and thus cell proliferation and some anti-apoptotic genes.

• In the brain, CREB plays a role in long-term memory and learning.

PI3K Signaling

• Cells continuously receive information ('signals') from their environment and from their neighbors. These signals are converted into intracellular 'second messenger signals' which ultimately make the cells respond by, for example, dividing, moving or even dying. Deregulated signaling is a hallmark of cancer cells.

• A key second messenger signal is the addition of phosphate groups to cellular components, a biochemical reaction carried out by kinases (1). Phosphoinositide 3-kinases (PI3Ks), a particular group of kinases which phosphorylate lipids. These lipids are pivotal second messengers which control a broad variety of cellular activities.

• Uncontrolled PI3K signaling is very common in cancer. PI3Ks also play principal roles in inflammation and diabetes. This makes these enzymes attractive targets for therapeutic intervention, and the development of drugs that alter PI3K action is being actively pursued.

• The first PI3K genes were isolated at the Ludwig Institute for Cancer Research [LICR]

• PI3K also contributes to angiogenesis---which in turn contributes to tumor growth.

• Increased production of PI3K leads to over production lipid secondary messengers that in turn stimulates signal transduction inappropriately leading to cell transformation [normal cell à cancerous cells]
  
  

Figure: PI3K Signaling

• The PI3K converts PIP₂ to PIP₃. Here PIP₃ is the lipid secondary messenger which in turn leads to cancer.

• PI3K Classes
  

Class I A consists of a catalytic subunit and a regulatory subunit. The catalytic subunit consists of p110α, p110β, or p110δ, while the regulatory subunit consists of p85α, p85β or p55γ.

Class I B consists of only one subunit: a p110γ catalytic unit and a p101 regulatory unit.

• In the above diagram, Class I A is activated by Tyrosine Kinase receptors, Antigen receptors or Integrin receptors. While Class I B is activated by G- Protein Coupled Receptors [GPCR]
• In response to activation by the above mentioned receptors PI3K produces lipid secondary messengers which activates the signal transduction. Signal transduction remains active till phosphatase enzyme [particularly PTEN gene] dephosphorylates the lipid secondary messenger.
• PTEN gene removes the unnecessary phosphates added by PI3K
• In many cancers the PTEN "brake" is deleted.

WNT Pathway

About Wnt:

• Wnt consists of a large family of cysteine-rich glycoproteins which are involved in early embryonic development.
• The term wnt is an amalgam of wingless (Wg) and int.
• Wg in Drosophila was found to be homologous to int in mice, and so the family name was changed to Wnt to reflect both origins.
  
  Wnt Pathway:

• The Wnt ligand binds to a particular receptor called the Frizzled receptors.

• The Frizzled receptor has mainly 3 domains:
  
  1. The extracellular Wnt-binding domain
  2. 7 transmembrane spanning regions
  3. Intracellular C-terminal tail
  
  Figure: Frizzled Receptor
  

• Because of the 7 transmembrane spanning regions, the receptor is called Serpentine receptor.

• Normally, excess of Beta-catenin [which binds cadherins to actin filaments* ] is degraded by a degradation complex [DC]. The DC phosphorylates Beta-catenin, which draws ubiquitin which in turn prepares beta-catenin for proteosome action. This degradation of beta-catenin will block beta-catenin from moving into the nucleus and thus blocks cell proliferation from taking place.

• However, when Wnt binds to the Frizzled receptor, the Frizzled receptor will get activated and this will in turn activate Dishevelled proteins [Dsh]. Dsh binds to one of the components of the degradation complex [DC] and thereby inactivating the complex. Therefore, the Beta-catenin will not be destroyed and it will enter the nucleus and interacts with TCF/LEF family of transcription factors to promote proliferation of cells.

• The component of the DC that the Dsh binds to is the GSK-3B [Glycogen Sythase Kinase- 3 –Beta]. GSK-3-B is in normal cells binds with APC [Adenomatosis Polyposis Coli] and Axin to form the degradation complex.
  
  * Points to note:
  
  
• E-Cadherins are proteins that hold homotypic cells together. Catenin's are their intracellular binding partners that bind them to Actin filaments.
• The ability of Catenin to bind to E-Cadherin and transcription factors is regulated by Tyrosine kinases or Serine kinases like GSK-3-B.
• When B-Catenin is not found in complex with Cadherin, it can form complexes with Axin [Component of Wnt pathway]. This then leads to the degradation of B-Catenin via the Wnt pathway mentioned above.