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PEA-15 and its Association with Diabetes and Cancer Jade Buchanan-Carter Aaron Buechlein Leo Senderowicz School of Informatics © 2006 Bioinformatics Indiana University April, 24th 2006 1 Outline • • • • • • Introduction Background and Motivation Association to Disease Potential for Drug Therapy Catpa Summary © 2006 Bioinformatics Indiana University April, 24th 2006 2 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary Introduction • 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 © 2006 Bioinformatics Indiana University April, 24th 2006 3 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary © 2006 Bioinformatics Indiana University April, 24th 2006 4 > Introduction What are Astrocytes? > Background & Motivation • Astrocytes are the most common type of glial cells in the nervous system > Disease Association • They have numerous projections that anchor neurons to their blood supply. > Therapeutic Agent > Catpa > Summary • 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. © 2006 Bioinformatics Indiana University April, 24th 2006 5 > Introduction > Background & Motivation Scop Classification > Disease Association > Therapeutic Agent > Catpa > Summary Class: All Alpha Fold: DEATH domain Superfamily: DEATH domain Family: DEATH effector domain © 2006 Bioinformatics Indiana University April, 24th 2006 6 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Catpa > Summary Death Effector Domain • Part of the Death effector Domain (DED) protein family which is generally associated with regulation of apoptosis. • CASP8 • FADD • CFLAR • Caspase 10 • DEDD • DEDD2 © 2006 Bioinformatics Indiana University April, 24th 2006 7 Binding > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary • 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. © 2006 Bioinformatics Indiana University April, 24th 2006 8 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent PEA-15 Phosphorylation • Unphosphorylated PEA15 is reported to be apoptotic, but the phosphorylated form is believed to be antiapoptotic. > Pathway > Catpa > Summary • 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. © 2006 Bioinformatics Indiana University April, 24th 2006 9 > Introduction > Background & Motivation Disease Association > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary • 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. © 2006 Bioinformatics Indiana University April, 24th 2006 10 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary Clinical Background of Diabetes • 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 gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. • In type 2 diabetes, not enough insulin produced or body ignores insulin action © 2006 Bioinformatics Indiana University April, 24th 2006 11 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary Diabetes type II study • 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). © 2006 Bioinformatics Indiana University April, 24th 2006 12 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary PEA15 associated cancers • 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). © 2006 Bioinformatics Indiana University April, 24th 2006 13 > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary Therapeutic Agent(s) • 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 Healthy © 2006 Bioinformatics Unhealthy Indiana University April, 24th 2006 14 > Introduction > Background & Motivation Omi/HtrA2 Phosphorylation at Ser-104 by PKC > Disease Association > Therapeutic Agent Phosphorylation at Ser-116 by CaKII or Akt Anti-Apoptotic Activity Increase in cell surface Glut1 PEA-15 Overexpression Inhibits glucose transport due to impairment of insulin-dependent Glut4 > Pathway FADD > Catpa ERK > Summary Elk1 Fas Type 2 Diabetes mellitus CELL PROLIFERATION Caspase 8/10 CREB mediated transcription APOPTOSI S © 2006 Bioinformatics Indiana University April, 24th 2006 15 > Introduction > Background & Motivation Curation Alignment Tool for Protein Analysis > Disease Association > Therapeutic Agent > Pathway CATPA DATA?? > Catpa > Summary CATPA © 2006 Bioinformatics Indiana University April, 24th 2006 16 Summary > Introduction > Background & Motivation > Disease Association > Therapeutic Agent > Pathway > Catpa > Summary • 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 © 2006 Bioinformatics Indiana University April, 24th 2006 17 Citations 1. 2. 3. 4. 5. 6. 7. 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 TNFαinduced 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 Questions © 2006 Bioinformatics Indiana University April, 24th 2006 19