Friday, July 27, 2012

PTEN

There have been many studies conducted related to the PTEN gene. These studies found that this gene plays a crucial role in normal cell functioning. However, mutation or lacking PTEN can lead to serious health conditions in the human body. Stem cell loss, deregulation and some forms of cancer are found to be caused by major changes in the PTEN gene. The PTEN gene belongs to the protein tyrosine phosphatase gene family.

Other Names


PTEN has other names aside from phosphatase and tensin homolog. It is also called PTEN1, PTEN_HUMAN, PTEN-MMAC1 protein, BZS, TEP1, TEP1 phosphatase, MHAM, MMAC1 and mutated in multiple advanced cancers 1.

(Image from: PTEN)

PTEN Functions


Phosphatase and tensin homolog is a protein encoded by the PTEN gene in humans. PTEN mutation can lead to the development of many types of cancer. The PTEN gene provides the instructions for enzyme production in all body tissues. This enzyme is a tumor suppressor. It ensures that cells divide and grow at a normal rate. Additionally, it removes the phosphate groups that consist of one phosphorus and three oxygen atoms. As a result, it modifies lipids and other proteins. In this mechanism of action, the PTEN enzyme is a phosphatase.


The PTEN gene plays a key role in chemical pathways during cell division and destruction. A good functioning gene signals the cells to divide and self-destruct. Moreover, PTEN has also been found to control cell migration or movement, the formation of new blood vessels and cell adhesion to surrounding tissues. Many studies found that PTEN has something to do with stabilizing cell genetic formation. Altogether, these functions effectively stop the uncontrolled cell growth that can otherwise lead to tumor formation.

The Clinical Significance of PTEN


Cancer stems from abnormal cell growth. A functioning PTEN gene can stop this cell mutation. In some types of cancer, the PTEN gene is either lost or dysfunctional. This means cell proliferation is increased, and cell death is reduced. PTEN has often been found to be inactive in cases of prostate cancer, endometrial cancer and glioblastoma. In fact, about 70 percent of men with prostate cancer have at least one missing PTEN gene at the time of diagnosis. Meanwhile, reduced PTEN expression is found in both lung and breast cancer. The PTEN mutation may also cause an inherited predisposition to cancer.

There are also certain non-cancerous conditions found to be caused by PTEN mutations. This includes Cowden syndrome. People with this condition have over 70 mutations in their PTEN gene. These mutations include missing base pairs. This stimulates the PTEN gene to produce proteins that are not functioning properly or not working at all. These dysfunctional proteins will not be able to control cell division and instruct abnormal cells to self-destruct. This condition often leads to tumor growth in the thyroid, breast and uterus.

Non-cancerous tumors like hamartomas are also caused by PTEN gene mutations. These tumors cause disorders like Proteus-like syndrome and Bannayan-Riley-Ruvalcaba syndrome. These disorders are called PTEN hamartoma tumor syndromes.


Recent studies have also shown that PTEN has a key role in the developmental disorder autism. PTEN mutation and abnormal changes were found in 3 out of 18 people with autism. This includes classical autism called Rett Syndrome and other similar conditions. Additionally, PTEN mutation is also evident in people who have an unusually large head circumference. This is known as macrocephaly. However, these findings still need to be verified. It is yet unclear as to how PTEN mutation leads to the development of these disorders.

People with PTEN mutations should be given extra care. They should get genetic counseling and testing for PTEN mutations. This is particularly true for people with Cowden syndrome and other disorders with manifesting PTEN abnormalities. With this, there is a high possibility that they can prevent the development of these disorders.


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Thursday, July 12, 2012

Wilms Tumor Is Rare and Treatable

(Image from: Wilms tumor is a cancerous tumor of the kidney that occurs in children)


Wilms tumor is a kind of cancer of the kidney, also known as nephroblastoma, that mostly affects children. Some cases do appear in adults. Of all kidney cancers, Wilms tumors are the most common type occurring in children. Nonetheless, there are only about 500 cases diagnosed each year in the United States and the incidence is about one in one million for people under the age of 15.

About 75 percent of children who are diagnosed with Wilms tumor are otherwise healthy. Symptoms of the disease include a palpable mass in the abdomen that is often first detected during a doctor’s visit, or by a parent. Often, there is no pain and the child appears healthy in other ways. Pain in the abdomen can occur in some cases, along with blood in the urine, unexplained fever, high blood pressure and constipation.

In about 25 percent of cases, Wilms tumor is associated with a group of genetic disorders known as WAGR. These result from abnormalities to a specific gene, WT1. This gene is associated with WAGR and Denys-Drash syndrome and is located on chromosome 11p13. Denys-Drash syndrome is a very rare form of kidney dis-function separate from the symptoms of Wilms.


A second gene, WT2, is associated with the Beckwith-Wiedemann syndrome and is located on chromosome 11p15. Beckwith-Wiedemann sufferers have enlarged organs, tongue and head and are at greater risk of Wilms tumor kidney cancer.

Several other genes have been identified which appear connected to inherited Wilms tumor. Gene FWT1, which is located on chromosome 17q, and FWT2, located on chromosome 19q are also implicated in genetic cases of Wilms tumor.


Other conditions associated with WAGR syndrome include aniridia in which the iris in the eye is missing. Problems with the urinary tract that are present at birth, and varying degrees of mental retardation, are also associated with WAGR, as well as hemihypertrophy which results in enlargement of one side of the body over the other.

Most cases of WAGR and Wilms tumor are diagnosed in children under the age of five. Children over the age of eight are rarely diagnosed. It is a form of cancer that responds well to treatment and 90 percent of patients live for five years or more. Complete recovery often occurs. Wilms tumor is diagnosed using ultrasound followed by CT and MRI scans. Ninety five percent of the time it only affects one kidney and remains contained.


Wilms tumor is first treated by assessing the stage of the tumor. The exact course of treatment will depend on the stage of the tumor’s development. Removing the kidney, if only one is affected, is often part of the treatment. If both kidneys are affected, the diseased tissue is removed leaving the healthy part of the kidney intact.

Chemotherapy is often prescribed as a follow up treatment and sometimes radiation therapy is also used. If the tumor is detected and treated in its early stages, Wilms tumor has a high rate of survival and recovery. Prognosis is worse if the cancer has spread to lungs, brain or other organs.

People of African descent are at a somewhat higher risk of acquiring Wilms tumor than other ethnic groups. It is also somewhat more common in siblings and twins, strengthening the possibility of a genetic basis. However, a complete understanding of the heritability of Wilms tumors is still ongoing. Clinical trials involving new drugs for treatment of Wilms tumors are underway and the genetic factors that contribute to the disease continue to be unraveled.

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Wednesday, July 11, 2012

p53

p53 is a 44 kilodalton protein encoded by the TP53 gene. It is a tumor suppressor with crucial roles in both the induction of apoptosis and the arrest of cell cycle. Consequently, at least half of all proliferating tumor cells contain one or two mutated copies of TP53. While the protein has a mass of 44 kilodaltons, the presence of numerous proline residues impairs linearization of the protein during SDS-PAGE, so p53 migrates more slowly than expected and has an apparent mass of 53 kilodaltons in western blots. Isoforms of p53 are found in nearly all mammalian tissues.


The expression and localization of p53 within a cell can be visualized through immunofluorescence using a polyclonal or site-specific monoclonal p53 antibody. While p53 is primarily localized in the nucleus when active, it is transported into the cytoplasm by the binding protein, MDM2, and may be faintly visible there when inactive. In some forms of cancer, including breast cancers and neuroblastomas, p53 aggregates in small cytoplasmic puncta, where it is "sequestered" from both degradation and its normal regulatory role within the nucleus.


When it is allowed to aggregate within the nucleus, p53 acts as a potent mediator of cell cycle, apoptosis, and DNA repair. A central DNA-binding domain is positively-charged with a zinc moiety and several arginine residues. This allows for the upregulation of repair genes and the suppresson of oncogenes such as LMO3. Over 200 genes are transcriptionally regulated by p53, and numerous nongenomic sites contain the p53 consensus sequence. During times of cellular stress, p53 arrests the cell cycle in the G1 phase until the cell's DNA has been repaired or the source of stress has been relieved. p53 halts the cell cycle by interacting with members of the E2F family of proteins and preventing progression through G1-S phase "checkpoints". If p53 is not inactivated, the cell becomes functionally senescent.

(Image from: The p53 response)


The role of p53 in apoptotic signaling primarily involves interaction with members of the ASPP protein family. The introduction of DNA damage or oncogene upregulation to a cell results in ASPP1 and ASPP2 expression. In humans the C-terminals of these proteins bind to p53. This activates the mitochondrial apoptotic pathway by activating PUMA (p53 upregulated modulator of apoptosis) and inhibiting activity of the antiapoptotic Bcl-2 protein. Conversely, expression of the iASPP (inhibitory ASPP) competes with and prevents ASPP1 and ASPP2 binding to p53 and is therefore antiapoptotic.


Perhaps the most well-researched aspect of p53 activity is its role as a tumor suppressor. This suppression is largely through p53's ability to halt cell division and induce apoptosis in cells (as in the case of E2F and ASPP proteins, respectively). p53 also interacts with YB1 (Y-box binding protein 1), which facilitates proliferation and inhibits apoptosis by downregulating p53 expression. Mutated forms of p53, including the forms seen in many cancer types, alter the interaction with YB1, causing YB1 to build up in the nucleus and inhibit p53 activity indefinitely, leading to proliferation and tumorigenesis. Thus, p53 is a potent tumor suppressor and its inactivation facilitates the development of tumors. Indeed, the anti-tumor effects of p53 are essential for long-term survival. The inactivation of a single parental copy of TP53 causes Li-Fraumeni syndrome, an autosomal dominant disorder characterized by the early onset of multiple forms of malignant cancer, especially sarcomas.


p53 expression is primarily regulated through the activity of the protein MDM2, which binds to the trans-activation domain at the N-terminal of the p53 protein. In normal cells, p53 has a half-life of under thirty minutes due to MDM2 binding, which exports p53 from the nucleus and marks it for ubiquitination and eventual proteolysis. However, during times of cell stress the MDM2 mechanism becomes dysregulated, leading to an increase in p53 protein levels. For instance, DNA damage activates DNA-damage kinases that lead to both auto-deregulation of MDM2 and the phosphorylation of p53, which disrupts MDM2 binding.


In cancer cells, p53 is often suppressed through the activation of cyclooxygenase-2 (COX-2), which inhibits apoptosis in these cells by phosphorylating MDM2 at ser166 to stimulate its degration of p53. COX inhibitors can enhance chemotherapy-induced apoptosis by downregulating MDM2. This results in slower p53 degradation and a gradual buildup of nuclear p53 levels, which enhances both the cell cycle arrest and apoptotic signaling mediated by the protein. Similarly, MDM2 antagonists such as Nutlin-3a increase the effectiveness of chemotherapeutic drugs by disinhibiting endogenous p53 activity.


Many types of cellular stress alter the localization of p53. This includes the administration of ionizing radiation, oxidative stress, hypoxia, and oncogene expression. These forms of stress cause a rapid upregulation and transnucleation of the p53 protein that can be visualized using a p53 antibody. Similarly, the myriad interactions of p53 with its DNA binding sites have been identified through chromatin immunoprecipitation using p53 antibodies on the homogenates of lightly-fixed tissue. Recent research indicates that p53 contains multiple isoforms created from splice variants of the TP53 gene that have varying affinities for MDM2 and can be identified through western blotting (in instances where the splice has a different protein length) or using a monoclonal antibody (where the epitope is absent in one of the isoforms). The presence of such isoforms may be indicative of certain forms of cancer.

References:

Braithwaite AW, Del Sal G, Lu X. Some p53-binding proteins that can function as arbiters of life and death. Cell Death Differ. 2006 Jun;13(6):984-93. Review.

Camus S, Ménendez S, Fernandes K, Kua N, Liu G, Xirodimas DP, Lane DP, Bourdon JC. The p53 isoforms are differentially modified by Mdm2. Cell Cycle. 2012 Apr 15;11(8):1646-55.

Lasham A, Moloney S, Hale T, Homer C, Zhang YF, Murison JG, Braithwaite AW, Watson J. The Y-box-binding protein, YB1, is a potential negative regulator of the p53 tumor suppressor. J Biol Chem. 2003 Sep 12;278(37):35516-23.

Lau L, Hansford LM, Cheng LS, Hang M, Baruchel S, Kaplan DR, Irwin MS. Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma. Oncogene. 2007 Mar 22;26(13):1920-31.

Menendez D, Inga A, Resnick MA. Potentiating the p53 network. Discov Med. 2010 Jul;10(50):94-100. Review.

Ohnstad HO, Paulsen EB, Noordhuis P, Berg M, Lothe RA, Vassilev LT, Myklebost O. MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines. BMC Cancer. 2011 May 30;11:211:1-11

Ostermeyer AG, Runko E, Winkfield B, Ahn B, Moll UM. Cytoplasmically sequestered wild-type p53 protein in neuroblastoma is relocated to the nucleus by a C-terminal peptide. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15190-4.

Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J. 2004 Apr 7;23(7):1547-56.

Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003 Mar;21(3):313-20. Review.

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Wednesday, July 4, 2012

Von Hippel-Lindau (VHL) Disease

Introduction


Von Hippel-Lindau (VHL) disease is characterized by tumors or growths in multiple body systems. Typically, these growths or lesions begin as blood vessel hypertrophy in the central nervous system (CNS) and eyes. These VHL lesions can cause symptoms such as headaches, nausea or balance issues. The VHL disease can progress into other body systems such as the renal system where cysts form as a potential precursor to renal cancer. VHL also affects the body's adrenal glands and pancreas, causing cysts to form within the gland that prevent proper functioning. Approximately one in 36,000 individuals is affected by VHL, making it a relatively rare disease.

Symptoms and Diagnosis


Diagnosis of VHL often occurs only after the patient begins to exhibit symptoms, which can be latent and present until well into adulthood. Symptoms include dizziness, ataxia, and tinnitus, hearing loss, vision disturbances and hypertension. Because these symptoms can also be attributed to other causes, the patient's course of treatment can be compromised. Treatment and excision of the VHL tumors should begin as expediently as possible. Diagnosis can be definitively made upon the revelation of one's genotype, for those with VHL often have a genetic mutation.

VHL and Genetics


VHL disease follows an autosomal dominant inheritance pattern where the VHL genetic mutation must be present on only one set of chromosomes from either parent. The VHL gene resides on chromosome 3's short arm. In individuals who do not have a VHL mutation, the VHL gene codes for a specific messenger RNA (mRNA) sequence that creates Von Hippel-Lindau proteins (pVHL) that the cell then uses for a variety of cellular functions, including tumor suppression. A mutation in the VHL gene changes the individual's genetic blueprint to mutate mRNA so that pVHL is suppressed or defective. The manner by which the suppression of pVHL affects the body systems allows the disease to be made manifest.

Pathophysiology of VHL Disease


While it might seem that the suppression of pVHL would not seriously affect the mechanism of action within the cell, pVHL is a potent protein that regulates a cell's activity in numerous ways. First, the suppression of pVHL cells' cytoplasm causes marked changes in the cells' recycling program. Essentially, pVHL pairs with other proteins and begins to ubiquitinate other materials, which marks them to be deconstructed. The marker indicates which materials are no longer crucial to the cell's actions, thereby preventing the cell from engaging in unrestricted growth.

(Image from: HIF Biology)


Defective pVHL allows the cell to continue its growth without restraint


A major cytoplasmic constituent that is targeted for destruction includes a factor that should degrade in the presence of oxygen. These factors, hypoxia-inducible factors 1 (HIF1) and hypoxia-inducible factors 2 (HIF2), play an enormous role in how the cell chooses to differentiate its growth. In low-oxygen environments, HIF encourages the cell to create more blood vessels in order to relieve the cell or tissue of hypoxia. If the HIF does not become targets for recycling by the pVHL, then the HIF continues to signal to the cell that it needs to create blood vessels even if the cell is properly oxygenated. These blood vessels form the tumors that are the foundation of the VHL disease state.

Genetic testing for VHL can greatly improve an affected individual's prognosis. Because VHL can be present for years before symptoms become tiresome enough to go to the physician, genetic testing and subsequent counseling can prove to be life-saving. Proper medical imaging and surgical options can not only reduce the severity of bothersome symptoms, they can also slow the progression of VHL into deadly carcinomas.


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Monday, July 2, 2012

Tumor Suppressors

(Image from: Tumor Suppressor Genes)


Our understanding of cancer and its triggers is still in its infancy. However, recent research offers new insights to better understand what causes cancer cells to proliferate. Of particular interest is tumor suppressor genes that help stop the uncontrolled cell division and growth that permit cancer-causing mutations. Moreover, these important cells also promote cell death, a necessary component in the life cycle of healthy cells. Of critical importance, these tumor suppressor genes also play a role in DNA repair, preventing the accumulation of mutations that may lead to the development of cancer. Considering the importance of these genes in preventing cancer, any disturbance in the functioning of these tumor suppressor genes can cause irreparable damage that might ultimately lead to cancer.

The Two-Hit Hypothesis


All genes, including cancer suppressor genes, are subjected to a number of mutations. Fortunately, in the case of cancer suppressor genes, the mutations that interfere with normal functioning are typically recessive. That is, for the mutation to lead to cancer, both tumor suppressor genes in a given cell must have the same mutation. In the early 1970s, Alfred Knudson coined the term “two-hit hypothesis” to describe this phenomenon.

Case Study: Retinoblastoma

Knudson, a geneticist, discovered this important concept while studying a rare type of cancer that strikes children. Known as retinoblastoma (Rb ), this cancer affects the retina, the part of the eye that detects light. Normally, retinoblasts, or immature cells in the retina, have stopped growing and dividing by the time an embryo has developed. At this point, retinoblasts typically become differentiated, resulting in distinct photoreceptor and nerve cells within the retina. In children with retinoblastoma, however, differentiation does not occur. Rather, the retinoblasts continue to divide, leading to the development of retinal tumors. Detection and treatment is essential because, as with other cancers, untreated retinoblastoma can metastasize and affect other parts of the body.

In order to better understand this ailment, Knudson conducted a 25-year study starting in the mid-1940s. In particular, Knudson wished to understand how parents diagnosed with retinoblastoma could have children free of the malady, but whose own children were later diagnosed with retinoblastoma. The geneticist took a closer look at two groups of patients. The first group was made up of 23 patients with bilateral hereditary retinoblastoma. In bilateral hereditary retinoblastoma, cancer is detected in both eyes there is a history of retinoblastoma in the family. The second group consisted of 25 patients with unilateral nonhereditary retinoblastoma.

Age at diagnosis became particularly important at this point because of the time necessary for mutations to occur and accumulate. If the cancer were the result of mutations in a single gene, then both copies would have to mutate at the same rate for the cancer to occur. Thus, patients who inherited one mutated gene allele would only need to accumulate one mutation on the other gene allele for the cancer to occur. Those who did not inherit the mutation would need to accumulate a mutation on both alleles, a process that would take considerably more time. He noted that for his patients, bilateral hereditary retinoblastoma was diagnosed earlier than the unilateral nonhereditary variety, supporting his hypothesis that two mutations were required. Originally dubbed the two-mutation hypothesis, this phenomenon is now known as the two-hit hypothesis.

Tumor Suppressor Gene Inactivation


The two-hit hypothesis is essential to understanding the process by which tumor suppressor genes become inactive or non-functioning. During a process known as loss of heterozygosity, or dissimilarity, the second copy of a tumor suppressor gene becomes inactive when the gene is “hit” again. That is, the functioning copy undergoes a mutation, making the pair homozygous, or similar, in terms of the mutated gene. With this double mutation, the tumor suppressor gene becomes unable to fulfill its normal function.

Advances in Understanding Tumor Suppressor Genes


Once scientists were able to map the human genome, they were able to identify the particular gene (Rb1) responsible for suppressing retinoblastoma tumor growth. Researchers then used mice to examine how the Rb1 gene works and what happens when two “hits” affect this gene. They have since identified a number of other tumor suppressor genes. Future research will focus on using this growing knowledge base to better diagnose and treat a variety of cancers.


Other tumor suppressor genes: p53, VHL, WT1, BRCA1, MLH1, PTEN

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