Abbiamo visto come p53 possa regolare a livello organismico sia la insorgenza di tumori che il mancato differenziamento di alcuni tessuti: dunque il controllo della progressione del ciclo è legata al differenziamento ed alla trasformazione tumorale. Abbiamo anche imparato il principio per cui una proteina ha moduli diversi che sono sfruttati da interattori (anche virali) ORA CI CHIEDIAMO, PERCHE LE CELLULE HANNO UNA VITA PREDETERMINATA?
Ras slide
Fuga dalla Senescenza, una cellula può accumulare mutazioni e diventare immortale
Il dilemma Dei Telomeri TELOMERI
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Cell death Distinguere necrosi da apoptosi
Dna laddering nell apoptosi TUNEL, teoria
TUNEL, PRATICA da qua Tunel staining, in vivo
Desc sympath system Da qui Teoria delle neurotrofine Da Montalcini. UN SARCOMA (TU) STIMOLA LA CRESCITA DI FIBRE DEL SIMPATICO
La storia del NGF Impianto di NGF nel cervello attira fibre del sistema simpatico Dipendenza dei neuroni da neurotrofine
Signaling del recettore trk LE TIROSINE CHINASI: pathway semplificato
Effetto NGF sui neuroni
Effetto neurotrofine sulla morfologia dei neuroni
Table I. Families of structurally related neurotrophic factors and their receptorsneurotrophic factor family Neurotrophic factor Preferred receptor(s) -------------------------------------------------------------------------------- Neurotrophins Nerve growth factor (NGF) TrkA, p75ntr Brain-derived neurotrophic factor (BDNF) TrkB, p75ntr Neurotropin-3 (NT3) TrkC, p75ntr Neurotrophin-4 (NT4) TrkB, p75ntr GDNF family Glial cell-derived neurotrophic factor (GDNF) Ret, GFR-1 Neurturin Ret, GFR-2 Artemin Ret, GFR-3 Persephin Ret, GFR-4 Neurotrophic cytokines Ciliary neurotrophic factor (CNTF) gp130, LIFRß, CNTFR Leukaemia-inhibitory factor (LIF) gp130, LIFRß Cardiotrophin-1 (CT-1) gp130, LIFRß Oncostatin-M (OSM) gp130, OSMRß Interleukin-6 (IL-6) gp130, IL6R HGF family Hepatocyte growth factor (HGF) Met Macrophage-stimulating protein (MSP) Ron -------------------------------------------------------------------------------- Although several neurotrophic factors bind and activate more than one member of a family of receptors (e.g. NT3 activates TrkA and TrkB in addition to its preferred receptor tyrosine kinase TrkC), for simplicity, only the preferred receptors for each factor are listed. Ch!!!!
Figure 1. Schematic diagram of the Activation of the Caspase Cascade. Apoptotic signals cause oligomerization of death adaptor proteins, which in turn oligomerize initiator procaspases. Oligomerized procaspases autoproteolytic activity result in active initiator caspase enzymes. Active initiator caspases then process and activate effector procaspases. Active effector caspases cleave various substrates necessary for apoptosis to proceed.
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MECCANISMI MOLECOLARI DELLA APOPTOSI: CARATTERIZZAZIONE BIOCHIMICA, INTRINSECA ED ESTRINSECA RUOLO DELLE CASPASI
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LINEAGE
LINEAGE SEMPLI FICATO
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The nuc-1 gene encodes a DNase II homolog similar to mammalian and Drosophila DNaseII enzymes and is required for DNA degradation during apoptosis as well as for degradation of dietary DNA during normal feeding; during apoptosis, NUC-1 functions in apoptotic cells at an intermediate stage of DNA degradation, after the killing step, but prior to cellcorpse engulfment Isolation of new ced mutations: Because living animals with undegraded cell corpses can be recognized using Nomarski optics but appear normal in general morphology and behavior (HEDGECOCK, SULSTON and THOMSON 1983), we used Nomarski microscopy to screen for new ced mutants.
Nel mutante Ced-1, le Cellule non sono fagocitate dopo la morte, I cadaveri rimangono Ced-3, Ced-1 double mutant, NO CADAVERI = Primo pathway apoptotico determinato geneticamente Da Horvitz, articolo originale The Caenorhabditis elegans gene ced-9 prevents cells from undergoing programmed cell death and encodes a protein similar to the mammalian cell-death inhibitor Bcl-2. We have cloned the C. elegans cell death gene ced-3. A ced-3 transcript is most abundant during embryogenesis, the stage during which most programmed cell deaths occur. The predicted CED-3 protein shows similarity to human and murine interleukin-1 betaconverting enzyme and to the product of the mouse nedd-2 gene, which is expressed in the embryonic brain. The sequences of 12 ced-3 mutations as well as the sequences of ced-3 genes from two related nematode species identify sites of potential functional importance. We propose that the CED-3 protein acts as a cysteine protease Here we identify a new gene, dark, which encodes a Drosophila homologue of mammalian Apaf-1 and Caenorhabditis elegans CED-4, celldeath proteins. Like Apaf-1, but in contrast to CED-4, Dark contains a carboxy-terminal WD-repeat domain necessary for interactions with the mitochondrial protein cytochrome c. Dark selectively associates with another protein involved in apoptosis, the fly apical caspase, Dredd. Dark-induced cell killing is suppressed by caspase-inhibitory peptides and by a dominant-negative mutant Dredd protein, and enhanced by removal of the WD domain. In the nematode C. elegans, genetic studies led to the discovery of 15 genes that function in programmed cell death 1 (Fig. 1). These 15 genes have been divided into four groups based on the order of their activity during the process of programmed cell death: (1) those involved in the decision making (ces-1 and ces-2); (2) in the process of execution (ced-3, ced-4, ced-9 and egl-1); (3) in the engulfment of dying cells by engulfing cells (ced-1, ced-2, ced-5, ced-6, ced-7, ced-10, ced-12); and (4) those in the degradation of cell corpses within engulfing cells (nuc-1).