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

TELOMERI

Il dilemma

Dei Telomeri

Da qua

Cell death

Distinguere necrosi da

apoptosi

Dna laddering nell’apoptosi

TUNEL, teoria

TUNEL, PRATICA da qua

Tunel staining, in vivo

Teoria delle neurotrofine

Desc sympath system

Da qui

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

LE TIROSINE CHINASI: pathway semplificato

Signaling del recettore trk

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)

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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

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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.

intrinseca

MECCANISMI MOLECOLARI DELLA APOPTOSI:

CARATTERIZZAZIONE BIOCHIMICA, INTRINSECA ED ESTRINSECA

RUOLO DELLE CASPASI

estrinseca

here

LINEAGE

LINEAGE

SEMPLI

FICATO

From here

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 cell-

corpse 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

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 beta-

converting 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, cell-

death 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).

Da Horvitz, articolo originale