Smad4 in Colon & Pancreatic Cancers

Slides:



Advertisements
Similar presentations
“ALL CELLS COME FROM PRE- EXISTING CELLS” Cell Division What are two different types of reproduction? WHAT MUST TAKE PLACE FOR A CELL OR ORGANISM TO.
Advertisements

Peutz-Jeghers Syndrome (PJS) and LKB1 Sarah Bass March 28,
BMP Receptor 1 : Juvenile Polyposis (Colon Cancer) Cecily Johnson Biology 169 March 24, 2005.
Presented by: Jacqueline Holt March 4th 2003
A tumor suppressor gene
Peutz-Jeghers Syndrome: LBK1/STK11 By Matt Wheeler.
Notch1 and pre-T-cell Acute Lymphoblastic Leukemia (T-ALL) by Lindsey Wilfley.
MSH2 and Human Nonpolyposis Colon Cancer Yael Aschner.
HNPCC and MLH1 Qi Peng Cancer Biology March 30 th, 2006.
ZAFIA ANKLESARIA Role of BMPR1A in Juvenile Polyposis Syndrome Biology 169.
SMAD4/DPC4: A Tumor Suppressor James Brooks March 23 rd, 2006.
LKB1 and Peutz-Jeghers Syndrome Josh Lawrimore. Gene Specifics.
34 Cancer.
Next lecture:techniques used to study the role of genes in develpoment Random genetics followed by screening Targeted mutagenesis (gene knockout) Transgenic.
Transforming Growth Factor β Receptor Type II Tina Morris
Phosphatase and Tensin Homolog Deleted on Chromosome 10
BMP receptor1a Amit Patel Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, Men 295,280 Women 275,000.
Copyright (c) by W. H. Freeman and Company Chapter 24 Cancer.
MDM2: Oncogene Chan Lee. Discovery of MDM2: starting with tumor suppressor p53.
BRCA2 Blue: Rad51; Green: BRCA2
Transforming Growth Factor-Beta Receptor 2 TGF-β receptor 2
Colon cancer is the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development
Colon cancer is the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development
BRCA Genes Dallas Henson.
Tumor Supressor Gene Non-functional TSG Mutations increasing risk of cancer “Loss of function” mutation Proto-oncogene Oncogene (Hyperactive or unregulated.
How Genes are Controlled Chapter 11. Human Cells…. All share the same genome What makes them different????
By the end of this lecture, students will learn: 1.Oncogenes 2.Tumor suppressor genes. 3.DNA Repair genes 4.Genes Associated with Cancer Intended Learning.
Colorectal carcinoma Dr.Mohammadzadeh.
TGF-β Receptor I/ALK5: An Attractive Therapeutic Target in Tumor Development By Jake Bridgers.
Β-Catenin, Cancer, and G Proteins Not Just for Frizzleds Anymore Ming Yang et al. PNAS Maria Domenica Castellone et al. Science
WT1 and Wilms Tumor Joshua Chen. Homozygous mutant mice are embryonic lethal and fail to develop kidneys and gonads, with additional defects in the heart,
TGF-β receptor 1 Anshul Badhwar. Transforming Growth Factor β - receptor type I / ALK5 Serine/Threonine kinase receptor.
BRCA1: Tumor Suppression and Breast Cancer A breast cancer cell dividing.
BRG-1 in Cancer BRG-1 is an ATPase subunit of the SWI/SNF class of chromatin remodeling complexes It has been found mutated in a number of cancer cell.
Chromatin remodelling ATPase Brg1 is an essential factor for the maintenance of the intestinal crypt stem cell and adenoma formation Aliaksei Holik.
BMP Receptor 1A Juvenile Polyposis Dayna Neo 3/21/13 Biol
BMPR1A Bone Morphogenetic Protein Receptor 1 A (Juvenile Polyposis & Colon Cancer) Hallie Wieters.
Benign Versus Malignant Tumors
CHAPTER 19 THE ORGANIZATION AND CONTROL OF EUKARYOTIC GENOMES Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings Section D: The.
Section S Tumor viruses and oncogenes
FANCD2 & the Fanconi Anemia Tumor Suppressor Pathway Shayna Purcell Joo et al., 333 (6040):
BMP receptor1A Presented by Jena Buchan
NF1 (Neurofibromatosis Type 1) Greg Hogan Ribbon Representation of NF1-333 Scheffzek, et al. (The EMBO Journal Vol. 17,pp , 1998) Structural.
Chromatin remodelling ATPase Brg-1 is an essential factor for the maintenance of the intestinal crypt stem cell and adenoma formation Aliaksei Holik.
Types of Genes Associated with Cancer
TSC1/Hamartin and Facial Angiofibromas Biology 169 Ann Hau.
PTEN (Cowden Syndrome) /.../ sld083.htm.
Cowden’s Disease and PTEN. Cowden’s Disease (CD)  A rare autosomal dominant disease similar to Lehrmitte-Duclos Disease (LDD) and Bannayan-Zonana Syndrome.
Tumor-suppressor genes Tumor-suppressor genes, function like brakes, keep cell numbers down, either by inhibiting progress through.
Colon cancer: the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development
A program of differential gene expression leads to the different cell types in a multicellular organism During embryonic development, a fertilized egg.
Kate Bradford BIOL 445 March 5, 2009
Peutz-Jeghers Syndrome and LKB1/STK11
HCDC4 functions as part of an E3 ligase in the ubiquitin-mediated degradation of proteins. Homologues: FBW7 (H. sapiens); Archipelago (D. melanogaster);
The Role of SMAD4 (DPC4) in Cancer
Regulation of the Cell Cycle & Cancer
What makes a mutant?.
Bone Morphogenetic Protein Receptor 1A (BMPR1A) and Juvenile Polyposis Syndrome Cara Davidson March 18, 2004.
Concept 18.5: Cancer results from genetic changes that affect cell cycle control The gene regulation systems that go wrong during cancer are the very same.
TSC1 in Facial Angiofibromas
Genetics of Cancer.
PTEN (a.k.a. MMAC1 and TEP1) and Cowden’s Disease
The Role of Patch in Basal Cell Carcinoma
PTEN Tumor Suppressor and Cancer
BMP Receptor 1a and Juvenile Polyposis Syndrome
Smad4 (Dpc4) in Colon Cancer
Volume 119, Issue 4, Pages (October 2000)
Neoplasia lecture 7 Dr Heyam Awad FRCPath.
TGF-β Pathway Inhibition Signals New Hope for Fanconi Anemia
Presentation transcript:

Smad4 in Colon & Pancreatic Cancers Michael Cox

Smad4 gene alterations in various types of human cancer M. Miyaki, T. Kuroki / Biochemical and Biophysical Research Communications 306 (2003) 799–804

Familial juvenile polyposis Stem cells reside at crypt bottom. Cells differentiate as they progress upward from crypt bottoms. Mutations in Smad4 can lead to polyp formation in crypts. Elena Sancho, Eduard Batlle, and Hans Clevers Annu. Rev. Cell Dev. Biol. 2004. 20:695–723

Familial juvenile polyposis Autosomal dominant disease. Hamartomatous polyps-benign but can lead to malignancy. Symptoms: Bleeding, diarrhea, abdominal cramps, anemia. Usually occurs in first decade of life. Smad4 mutations are only one of many causes. No significant risk of cancer until multiple polyps form (>5). Can be treated by colectomy. http://www.clevelandclinic.org/registries/inherited/jp.htm http://www.mountsinai.on.ca/care/fgicr/kidskorner/jp

Smad4 Gene Member of Smad family (1-8), which mediates TGFβ signaling pathway. Only known mammalian co-Smad 552 amino acids long Contains 11 exons Locus at 18q21.1 Homology to Drosophila Mad & C. elegans sma-2/3/4. http://ghr.nlm.nih.gov/gene=smad4

TGFβ Signaling Pathway K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62

Smad4 Protein Acts as trimer, forms complexes with Smad2/3 M. Miyaki, T. Kuroki / Biochemical and Biophysical Research Communications 306 (2003) 799–804 Acts as trimer, forms complexes with Smad2/3 Smad2/3/4 proteins contain MH1 & MH2 regions at amino & carboxyl-terminals, respectively. MH1: DNA binding MH2: homo- and hetero-oligomerization Smad4 binding element (SBE): 5’-GTCTAGAC-3’

Smad4 Knockout Mice Homozygous mutants embryonic lethal at day 7.5 Disorganized endoderm and extraembryonic regions. Could rescue embryos with wt-visceral endoderm in tetraploid aggregation experiments. Rescued embryos had defects in anterior/posterior patterning. Could find no strong correlation between embryonic functions and tumor suppressor role as adult. Sirard et al. GENES & DEVELOPMENT 12:107–119 © 1998

Smad4 Knockout Mice Smad4 heterozygotes (+/-) were fertile and normal up to 1 year old. 50 weeks- gastric polyp development in 3 of 15 Smad4 (+/-) mice. 100 weeks- gastric polyp development in 15 of 15 Smad4 (+/-) mice. Duodenal polyps in mice of 50+ weeks.

Role in Cancer Progression APC-Adenomatosis polyposis coil Taketo et al.- meiotic recombination to form APC/Smad4 cis-heterozygotes. APC (+/-) Smad4 (+/-) polyps much larger than APC (+/-) Smad4 (+/+) mutants. Development into adenocarcinomas in cis-compounds, not in simple APC mutants. Inactivation of Smad4 results in malignant progression of intestinal polyps initiated by activation of APC gene. M. Miyaki, T. Kuroki / Biochemical and Biophysical Research Communications 306 (2003) 799–804

Role in Cancer Progression M. Miyaki, T. Kuroki / Biochemical and Biophysical Research Communications 306 (2003) 799–804

Overexpression of Smad4 in Pancreatic Cancer Overexpression of Smad4 using a viral vector lead to suppressed tumor growth in certain pancreatic cancer cell lines Peng et al. Clinical Cancer Research Vol. 8, 3628-3638, November 2002

Smad4 restoration in colon cancer cells leads to suppression of Wnt/β-catenin and migragtion. Xiaoxiao Tian et al. Biochemical and Biophysical Research Communications Volume 380, Issue 3, 13 March 2009, Pages 478-483

Smad4 Inhibition 1) Inhibition by Smad6/7 M. Miyaki, T. Kuroki / Biochemical and Biophysical Research Communications 306 (2003) 799–804 1) Inhibition by Smad6/7 2) Removal from nucleus by monoubiquitination. Ectodermin/TiF1γ-ubiquitinase FAM/Usp9x-deubiquitinase Jeffrey L. Wrana1,*Cell 136, January 9, 2009 ©2009 Elsevier Inc.

Smad4 Summary Only mammalian co-Smad of the Smad family. An important molecule in the TGFβ signaling pathway. Common in JPS, pancreatic, & colon cancers. Loss of Smad4 function occurs at later stages of malignancy. Overexpression can suppress tumor growth and migration in certain cancer cell lines. Inhibited by Smad6/7 and monoubiquitination.