1 / 19

Jade Buchanan-Carter Aaron Buechlein Leo Senderowicz School of Informatics

PEA-15 and its Association with Diabetes and Cancer. Jade Buchanan-Carter Aaron Buechlein Leo Senderowicz School of Informatics. © 2006 Bioinformatics Indiana University April, 24 th 2006. 1. Outline. Introduction Background and Motivation Association to Disease

kare
Download Presentation

Jade Buchanan-Carter Aaron Buechlein Leo Senderowicz School of Informatics

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. PEA-15 and its Association with Diabetes and Cancer Jade Buchanan-CarterAaron BuechleinLeo SenderowiczSchool of Informatics © 2006 Bioinformatics Indiana University April, 24th 2006 1

  2. Outline • Introduction • Background and Motivation • Association to Disease • Potential for Drug Therapy • Catpa • Summary © 2006 Bioinformatics Indiana University April, 24th 2006 2

  3. Introduction > Introduction > Background & Motivation • Phosphoprotein enriched in astrocytes 15 • Located on Chromosome 1 specifically at 1q21.1 • Originally identified by Chneiweiss and colleagues. • Most highly expressed in the nervous system • Particularly high levels in astrocytes and neurons of the hippocampus > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 3

  4. > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 4

  5. What are Astrocytes? > Introduction > Background • Astrocytes are the most common type of glial cells in the nervous system • They have numerous projections that anchor neurons to their blood supply. • They regulate the external chemical environment of neurons by removing excess ions, notably potassium, and recycling neurotransmitters released during synaptic transmission. • Actually outnumber neurons ten to one. & Motivation > Disease Association > Therapeutic Agent > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 5

  6. Scop Classification > Introduction > Background & Motivation > Disease Class: All Alpha Fold: DEATH domain Superfamily: DEATH domain Family: DEATH effector domain Association > Therapeutic Agent > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 6

  7. Death Effector Domain >Introduction >Background & Motivation > Disease • Part of the Death effector Domain (DED) protein family which is generally associated with regulation of apoptosis. • CASP8 • FADD • CFLAR • Caspase 10 • DEDD • DEDD2 Association > Therapeutic Agent > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 7

  8. Binding > Introduction > Background & Motivation • PEA15 contains two phosphorylation sites. • Ser104 and Ser116 • Ser116 is phosphorylated by calcium-calmodulin kinase II and also by Akt (protein kinase B) • Ser104 is phosphorylated by protein kinase C • PEA15 is reported to bind FADD via its death domain, blocking its ability to recruit caspases thus preventing cell death. • PEA15 is also reported to bind ERK1/2, a MAP kinase, retaining ERK in the cytoplasm. > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 8

  9. PEA-15 Phosphorylation > Introduction > Background & Motivation > Disease • Unphosphorylated PEA15 is reported to be apoptotic, but the phosphorylated form is believed to be antiapoptotic. • Phosphorylated at both Ser104 & 116, PEA15 blocks its interaction with ERK1/2 • Phosphorylated at Ser104, PEA15 blocks ERK binding • Phosphorylated at Ser116, PEA15 promotes FADD binding. Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 9

  10. DiseaseAssociation > Introduction > Background & Motivation > Disease Association > Therapeutic • Type II Diabetes • Over expression of PEA15 has been found to inhibit • insulin-stimulated glucose transport. • Cancer • Found to be overexpressed in cell lines associated with • Breast Cancer, Glioma, and Squamous Carcinoma. • Hypothesized to prevent cellular apoptosis and/or • promote cell proliferation. Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 10

  11. Clinical Background of Diabetes > Introduction > Background & Motivation > Disease • Previously called non–insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. • Accounts for about 90% to 95% of all diagnosed cases of diabetes. • Associated with older age, obesity, family history of diabetes, history of gestationaldiabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. • In type 2 diabetes, not enough insulin produced or body ignores insulin action Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 11

  12. Diabetes type II study > Introduction > Background & Motivation > Disease • Overexpression of the ped/pea-15 gene causes diabetes by impairing glucose-stimulated insulin secretion in addition to insulin action. • Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. • Stable overexpression of ped/pea-15 in the glucose-responsive MIN6 beta-cell line also caused protein kinase Calpha activation and a marked decline in glucose-stimulated insulin secretion. • Antisense block of endogenous ped/pea-15 increased glucose sensitivity by 2.5-fold in these cells • Cells rescued by the protein kinase C inhibitor bisindolylmaleimide (Ser104). Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 12

  13. PEA15 associated cancers > Introduction > Background & Motivation > Disease • A glioma is a type of primary central nervous system (CNS) tumor that rises from glial cells. • Squamous Cell Carcinoma: affects tissues such as skin, the esophagus, the lungs, and the cervix. - 200,000 people in the United States alone every year. Smoking is a significant risk factor. • Breast Cancer - Most common form of cancer in females (worldwide) - affects one out of eleven women in the western world. - genetic factors (i.e. DNA damage of BRCA1,BRCA2) and environmental factors (alcohol, birth control pills). Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 13

  14. Therapeutic Agent(s) > Introduction > Background • Dominant negative expression of AKT increases apoptosis • in vitro • Thus, promoting apoptosis via inhibition of AKT • phosphorylation can be used as drug therapy • Targeting the PI3K(phosphoinositol-3-kinase) pathway is the • strategy available in literature • LA (leuprolide acetate) inhibits phophorylation of AKT which • leads to inhibition of phosphorylation on Ser116 of PEA15 • which increases apoptosis • Rapamycin also targets PI3K pathway and slows down • tumor growth without significant side effects in animal • models & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary Healthy Unhealthy © 2006 Bioinformatics Indiana University April, 24th 2006 14

  15. Phosphorylation at Ser-116 by CaKII or Akt Omi/HtrA2 > Introduction Phosphorylation at Ser-104 by PKC Anti-Apoptotic Activity > Background & Motivation Increase in cell surface Glut1 > Disease PEA-15 Association Overexpression > Therapeutic Agent Inhibits glucose transport due to impairment of insulin-dependent Glut4 > Pathway FADD > Catpa ERK > Summary Elk-1 Fas CELL PROLIFERATION Type 2 Diabetes mellitus Caspase 8/10 CREB mediated transcription APOPTOSIS © 2006 Bioinformatics Indiana University April, 24th 2006 15

  16. Curation Alignment Tool for Protein Analysis > Introduction > Background & Motivation > Disease CATPA Association > Therapeutic Agent > Pathway CATPA DATA?? > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 16

  17. Summary > Introduction > Background & Motivation > Disease • Excess of PEA15 in cells reduces apoptosis and promotes cell proliferation via binding to FADD and ERK1/2 respectively • Study of these pathways may lead to discovery of therapeutic agents for treatment of cancer and diabetes Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 17

  18. Citations • Tibbetts, M., Zheng, L., Lenardo, M. The death effector domain protein family: regulators of cellular homeostasis. Nature 4, 404-409 (2003). • Ramos, J.W., PEA-15 Phosphoprotein: A potential cancer drug target. Hawaii Med. J. 64, 77-79 (2005). • Kitsberg, K. et al. Knock-Out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFα-induced apoptosis. The J. of Neuroscience 19, 8244-8251 (1999). • Underhill, D.A., Vogan, K.J., Underhill, T.M., Gros, P., Identification of a novel, alternatively spliced isoform and single nucleotide polymorphisms in the murine Pea-15 gene. Mammalian Genome 12, 172-174 (2001). • Renganathan, H., Vaidyanathan, H., Knapinska, A., Ramos, J.W., Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. Biochem. J. 390, 729-735 (2005). • Wolford, J.K., Bogardus, C., Ossowski, V., Prochazka, M., Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians. Gene 241, 143-148 (2000). • Condorelli, G., Vigliotta, G., Iavarone, C., Caruso, M., Tocchetti, C.G., Andreozzi, F., Cafieri, A., Tecce, M.F., Formisano, P., Beguinot, L., Beguinot, F., PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. The EMBO J. 17, 3858-3866 (1998). © 2006 Bioinformatics Indiana University April, 24th 2006 18

  19. Questions © 2006 Bioinformatics Indiana University April, 24th 2006 19

More Related