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Novel regulation of the common tumor suppressor PTEN
January 12, 2007PTEN is one of the most commonly mutated tumor suppressor genes. It is an antagonist for many cellular growth, proliferation and survival processes. When mutated or deleted, it causes cancers of the prostate, breast, colon, and brain. Researchers led by scientists at Memorial Sloan-Kettering Cancer Center have now identified fundamentally novel regulatory mechanisms of PTEN function. The findings from two related studies are published in the January 12 issue of Cell.
The first is research by Dr. Xuejen Jiang's laboratory at Sloan-Kettering which identified a novel component that regulates PTEN. This protein, NEDD4-1, controls protein stability in cells. Researchers found that NEDD4-1 is a key component in eliminating PTEN from cells by adding a molecular tag, ubiquitin, to PTEN causing degradation in the cellular machinery called proteasome. In a mouse model for prostate cancer, the researchers found that areas with aggressive tumor contained low PTEN levels and high NEDD4-1. They concluded that NEDD4-1 could promote cancer development by down-regulating PTEN.
The second study by Dr. Pier Paolo Pandolfi of Memorial Sloan-Kettering and colleagues found that the ubiquitination of PTEN by NEDD4-1 also regulates another important aspect of PTEN, its cellular localization.
PTEN has been found mostly in the cytoplasm but has been known to also be in cell nuclei. While the cytoplasmic function of PTEN is now quite well understood, its nuclear functions have been elusive. Looking at a family with an inherited PTEN mutation that caused them to have the cancer-susceptibility condition, Cowden Syndrome, researchers found that the patients' colon cancer strikingly lacked nuclear PTEN.
The Pandolfi and Jiang labs showed that the PTEN mutation in these patients prevented the addition of ubiquitin by NEDD4-1, providing a molecular mechanism for the detrimental effect of the mutant PTEN protein. They showed that the single ubiquitin tagging is necessary to import PTEN into the cell nucleus where it is protected from degradation and cancer is initiated.
According to the researchers, the uncovered key role of PTEN degradation provides a new therapeutic strategy. Since ubiquitination has both positive (single tag) and negative (repetitive tagging) effects, a class of drugs, the proteasome inhibitors, that selectively blocks the degrading effects of ubiquitination, should now be studied as possible treatments for cancers with PTEN mutations.
Memorial Sloan-Kettering Cancer Center
PTEN has been found mostly in the cytoplasm but has been known to also be in cell nuclei. While the cytoplasmic function of PTEN is now quite well understood, its nuclear functions have been elusive. Looking at a family with an inherited PTEN mutation that caused them to have the cancer-susceptibility condition, Cowden Syndrome, researchers found that the patients' colon cancer strikingly lacked nuclear PTEN.
The Pandolfi and Jiang labs showed that the PTEN mutation in these patients prevented the addition of ubiquitin by NEDD4-1, providing a molecular mechanism for the detrimental effect of the mutant PTEN protein. They showed that the single ubiquitin tagging is necessary to import PTEN into the cell nucleus where it is protected from degradation and cancer is initiated.
According to the researchers, the uncovered key role of PTEN degradation provides a new therapeutic strategy. Since ubiquitination has both positive (single tag) and negative (repetitive tagging) effects, a class of drugs, the proteasome inhibitors, that selectively blocks the degrading effects of ubiquitination, should now be studied as possible treatments for cancers with PTEN mutations.
Memorial Sloan-Kettering Cancer Center
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The p53 Tumor Suppressor Pathway and Cancer (Protein Reviews, Vol. 2) by Gerard P. Zambetti (Editor) The p53 tumor suppressor gene is mutated in approximately half of all human malignancies, including colon, lung, and breast cancers. It is well recognized that these mutations directly inactivate p53 tumor suppressor function. Furthermore, the p53 protein operates within a pathway and this pathway, including the mutations in p53, is likely inactivated by nearly every human tumor. In support of this hypothesis, 100% of mice that have been engineered such that they do not express p53 protein (knockout animals), develop highly malignant tumors by only 3-6 months of age. The importance of p53 in preventing human cancer is also evident by families in which a mutated p53 gene is inherited from a parent. Individuals who carry an inherited germline p53 mutation are associated with Li-Fraumeni... |
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Benign Prostatic Hyperplasia AHCPR Clinical Practice Guideline/Tumor Suppressor Genes in Human Cancer (NCME Video 658) Also With: Network For Continuing Medical Education (Primary Contributor), John Wasson (Primary Contributor), Daniel A Haber (Primary Contributor) In February, 1994, the Agency for Health Care Policy and Research (AHCPR) released a clinical practice guideline dealing with the diagnosis and treatment of benign prostatic hyperplasia. This telecourse presents highlights of that guideline. In the 1980's, the study of positive oncogenes was a major focus in the quest to understand the molecular origins of cancer. Today, tumor suppressor genes are sharing the spotlight and may exemplify an untapped resource for anticancer therapy. Dr. Haber demonstrates how recessive oncogenes, which normally control cell growth, allows cells to progress to malignancy when lost or inactivated. |
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Tumor Suppressor Genes by Katherine R. Polinsky (Editor) A tumour suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. A mutation or deletion of such a gene will increase the probability of the formation of a tumor. Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis', which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53. Tumor suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive... |
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Tumor Suppressor Genes: An entry from Macmillan Reference USA's Macmillan Reference USA Science Library: Genetics by Giles Watts (Author) This digital document is an article from Macmillan Reference USA Science Library: Genetics, brought to you by Gale®, a part of Cengage Learning, a world leader in e-research and educational publishing for libraries, schools and businesses. The length of the article is 1047 words. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. A comprehensive collection of articles on all aspects of genetics, from Mendel to the decoding of the human genome. Explains the workings of genes and chromosomes, genetic diseases, and biotechnology. Covers the ethical, legal, and social issues connected to genetic science and includes coverage of careers in the field. | |
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Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA ... from: Environmental Health Perspectives by Lamia Benbrahim-Tallaa (Author), Robert A. Waterland (Author), Anna L. Dill (Author), Mukta M. Webber (Author), Michael P. Waalkes (Author) This digital document is an article from Environmental Health Perspectives, published by Thomson Gale on October 1, 2007. The length of the article is 4339 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA methyltransferase.(Research)(deoxyribonucleic acid)(Clinical report) Author: Lamia Benbrahim-Tallaa Publication: Environmental Health Perspectives (Magazine/Journal) Date: October 1, 2007 Publisher: Thomson... | |
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Oncogenes and Tumor Suppressor Genes in Human Malignancies (Cancer Treatment and Research) by C.C. Benz (Editor), E.T. Liu (Editor) This volume begins by reviewing selected malignancies in which the search for clinically relevant oncogenes has led to more focused studies on gain-of-function and loss-of-function genetic abnormalities, as well as autocrine and paracrine growth factor loops known to regulate tumor physiology and malignant cell behavior. Many of these genetic and functional abnormalities are shared by several different tumor types and are not uniformly present in all tumors of the same type. This observation brings up molecular questions about the tissue-specific determinants that underlie individual cancers and also gives added impetus to the suggestion that molecular abnormalities (referred to as tumor markers) be included among the histopathologic features used for clinical diagnosis and... | |
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Tumor Suppressor Genes (Immunology Series) by George Klein (Editor) | |
![Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: Deduction from structural analysis ... for deletions [An article from: DNA Repair]](http://ecx.images-amazon.com/images/I/51FZ3K9Y7XL._SL160_.jpg) |
Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: Deduction from structural analysis ... for deletions [An article from: DNA Repair] by T. Kohno (Author), J. Yokota (Author) This digital document is a journal article from DNA Repair, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Chromosome interstitial deletion (i.e., deletion of a chromosome segment in a chromosome arm) is a critical genetic event for the inactivation of tumor suppressor genes and activation of oncogenes leading to the carcinogenic conversion of human cells. The deletion at chromosome 9p21 removing the p16 tumor suppressor gene is a genetic alteration frequently observed in a variety of human cancers. Thus, structural analyses of breakpoints for p16 deletions in several kinds of human cancers have been performed to elucidate the... |
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Tumor Suppressor Genes and Cell Proliferation Control in the Carcinogenesis of the Oral Mucosa by Sabine Christiane Girod (Author) This text is aimed at those involved with cancer research, particularly those interested in epithelial cancers of the aerodigestive tract accounting for one third of all cancer deaths each year. The recent discovery of two groups of genes, oncogenes and tumour suppresor genes has thrown doubt on the possibility of a genetic predisposition in all cases. The current knowledge and recent results concerning the role of tumour suppressor genes in oral carcinogenesis are described, as is the importance of understanding the basic principles and the application of molecular biology techniques. | |
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Tumor Suppressor Genes: Volume 1: Pathways and Isolation Strategies (Methods in Molecular Biology) by Wafik S. El-Deiry (Editor) Univ. of Pennsylvania, PA. Text covers all the known tumor suppressor pathways and provides key information on their discoveries, analysis, and their uses in cancer therapeutics. Focuses on TSGs and the relevance of the biochemical pathways they regulate to human cancer. For researchers. DNLM: Genes, Tumor Suppressor--physiology. |
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