About Aging Pathway Atlas Searching DB Data Input Gene Ontology

  Protein interaction map [Image] [Pajek] [NET]
  Reactive oxygen species intergrated pathway (NFkB, HIF-1a, AP-1)
  Apoptosis pathway on mitochondira
Protein interaction map

In order to see the interaction of all proteins existing in the AgingPath, we constructed a map based on a graphic algorithm.The node color varies with number of interactions with other nodes; red indicates seven interactions; reddish-yellow, six; pink, five; brown, four; green, three ; yellow, two ; and black, one. Further we will be programming in process to isolate each individual protein and various nodes that interacts with each other, using JAVA.

ROS intergrated pathway

Nuclear Factor - kappa B.
NF-kB is a nuclear transcription factor that regulates expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorigenesis, inflammation, and various autoimmune diseases. The activation of NF-kB is thought to be part of a stress response as it is activated by a variety of stimuli that include growth factors, cytokines, lymphokines, UV, pharmacological agents, and stress. In its inactive form, NF-kB is sequestered in the cytoplasm, bound by members of the IkB family of inhibitor proteins, which include IkBa, IkBb, IkBg, and IkBe. The various stimuli that activate NF-kB cause phosphorylation of IkB, which is followed by its ubiquitination and subsequent degradation. This results in the exposure of the nuclear localization signals (NLS) on NF-kB subunits and the subsequent translocation of the molecule to the nucleus. In the nucleus, NF-kB binds with a consensus sequence (5'GGGACTTTCC-3') of various genes and thus activates their transcription. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins; IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB leading to its ubiquitination and degradation. Tumor necrosis factor (TNF) which is the best-studied activator binds to its receptor and recruits a protein called TNF receptor death domain (TRADD). TRADD binds to the TNF receptor-associated factor 2 (TRAF-2) that recruits NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 have canonical sequences that can be phosphorylated by the MAP kinase NIK/MEKK1 and both kinases can independently phosphorylate IkBa or IkBb. TRAF-2 also interacts with A20, a zinc finger protein whose expression is induced by agents that activate NF-kB. A20 functions to block TRAF2-mediated NF-kB activation. A20 also inhibits TNF and IL-1 induced activation of NF-kB suggesting that it may act as a general inhibitor of NF-kB activation. (Chun Wu, Peter Dias and Bill Mills. Usha Ponnappan, PhD. U of Arkansas - http://www.biocarta.com/)

Hypoxia Inducible Factor - 1 alpha.
Hypammalian development, physiology and disease pathogenesis. The HIF-1 alpha subunit is subjected to oxygen-dependent ubiquitination and proteasomal degradation that is mediated by the von Hippel-Lindau protein. Interaction of HIF-1 alpha transactivation domains with coactivators is induced by hypoxia. The signal transduction pathway remains enigmatic, but involves generation of reactive oxygen species. Nitric oxide induces HIF-1 alpha under non-hypoxic conditions but inhibits hypoxia-induced HIF-1 alpha expression.(Curr Opin Cell Biol 2001 Apr;13(2):167-71)

Activator Protein 1
Vinblastine and other microtubule inhibitors are important oxia-inducible factor 1 (HIF-1) is an oxygen-regulated transcriptional activator that plays essential roles in mantitumor agents that cause mitotic arrest, and induce apoptosis through poorly understood mechanisms, in a wide variety of cell lines. The activating protein 1 (AP-1) transcription factor is a major target of the c-Jun NH2-terminal kinase (JNK) signaling pathway, which is activated by microtubule inhibitors.(Biochem Pharmacol. 2001 Sep 1;62(5):581-91.)

Apoptosis pathway on mitochondria

Apoptosis - death domain
Oilgomerization by specific death ligands ( TNF, FasL, Apo2L) recruits adaptor molecules involved in activation of caspase-8. The active caspase-8 activates executioner caspase, including caspase-3 and induces apoptosis.

Apoptosis - ROS stress
Reactive oxygen species (ROS) modulates bcl-2 family proteins to release cytochrome c from mitochondria. The multimeric complex formation of cytochrome c, APAF-1 and caspase 9 activates downstream caspases leading to apoptotic cell death.