Oncogeni: fattori di crescita

Transcription

1 Oncogeni: fattori di crescita

2 Oncogeni: recettori per fattori di crescita

3 Oncogeni: trasduttori del segnale

4 Oncogeni: fattori trascrizionali

5 Meccanismo di azione degli oncogeni 2 recettore 2 per il fattore di crescita epidermico umano 1 3 proto-oncogene (c-sis; sis = simian sarcoma) 4

6 Analisi del trascrittoma

7 Schematic illustration of the role of cyclins CDKs, and cyclin-dependent kinase inhibitors in regulating the G1/S cell-cycle transition. External signals activate multiple signal transduction pathways, including those involving the MYC and RAS genes, which lead to synthesis and stabilization of cyclin D (there are several D cyclins, but, for simplification, we refer to them as "cyclin D"). Cyclin D binds to CDK4, forming a complex with enzymatic activity (cyclin D can also bind to CDK6, which appears to have a similar role as CDK4). The cyclin D-CDK4 complex phosphorylates RB, located in the E2F/DP1/RB complex in the nucleus, activating the transcriptional activity of E2F (E2F is a family of transcription factors, which we refer to as "E2F"), which leads to transcription of cyclin E, cyclin A and other proteins needed for the cell to go through the late G1 restriction point. The cell cycle can be blocked by the Cip/Kip inhibitors p21 and p27 (red boxes) and the INK4A/ARF inhibitors p16ink4a and p14arf (green boxes). Cell-cycle arrest in response to DNA damage and other cellular stresses is mediated through p53. The levels of p53 are under negative regulation by MDM2, through a feedback loop that is inhibited by p14arf.

8 Ciclo cellulare e punti di restrizione

9 Expression of cyclin-cyclin-dependent kinase (CDK) complexes during the cell cycle. The phases of the cycle are indicated inside the arrows.

10 Main Cell-Cycle Components and Their Inhibitors Cell-Cycle Component Cyclin-Dependent Kinases CDK4 CDK2 CDK1 Inhibitors Cip/Kip family: p21, p27 1NK4/ARF family: p16ink4a, p14arf Checkpoint Components p53 Ataxia-telangiectasia mutated (ATM) Main Function Forms a complex with cyclin D. The complex phosphorylates RB, allowing the cell to progress through the G 1 restriction point. Forms a complex with cyclin E in late G 1, which is involved in the G 1 /S transition. Forms a complex with cyclin A at the S phase that facilitates the G 2 /M transition. Forms a complex with cyclin B, which acts on the G 2 /M transition. Block the cell cycle by binding to cyclin-cdk complexes. p21 is induced by the tumor suppressor p53. p27 responds to growth suppressors such as transforming growth factor-β. p16ink4a binds to cyclin D-CDK4 and promotes the inhibitory effects of RB. p14arf increases p53 levels by inhibiting MDM2 activity. Tumor suppressor altered in the majority of cancers; causes cell-cycle arrest and apoptosis. Acts mainly through p21 to cause cell-cycle arrest. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively regulated by MDM2 through a feedback loop. p53 is required for the G 1 /S checkpoint and is a main component of the G 2 /M checkpoint. Activated by mechanisms that sense double stranded DNA breaks. Transmits signals to arrest the cell cycle after DNA damage. Acts through p53 in the G 1 /S checkpoint. At the G 2 /M checkpoint, it acts both through p53-dependent mechanisms and through the inactivation of CDC25 phosphatase, which disrupts the cyclin B-CDK1 complex. Component of a network of genes that include BRCA1 and BRCA2, which link DNA damage with cell-cycle arrest and apoptosis.

11 Inherited Predisposition to Cancer Inherited Cancer Syndromes (Autosomal Dominant) RB p53 p16ink4a APC Gene Retinoblastoma Inherited Predisposition Li-Fraumeni syndrome (various tumors) Melanoma Familial adenomatous polyposis/colon cancer NF1, NF2 Neurofibromatosis 1 and 2 BRCA1, BRCA2 Breast and ovarian tumors MEN1, RET Multiple endocrine neoplasia 1 and 2 MSH2, MLH1, MSH6 PATCH Familial Cancers Hereditary nonpolyposis colon cancer Nevoid basal cell carcinoma syndrome Familial clustering of cases, but role of inherited predisposition not clear for each individual Breast cancer Ovarian cancer Pancreatic cancer Inherited Autosomal Recessive Syndromes of Defective DNA Repair Xeroderma pigmentosum Ataxia-telangiectasia Bloom syndrome Fanconi anemia neoplasie cutanee alta frequenza nella rottura e nel riarrangiamento dei cromosomi

12 Patogenesi del retinoblastoma (locus RB su cromosoma 13q14) Patologia oculare, e rappresenta il tumore maligno con maggiore diffusione in età pediatrica

13 Trasformazione neoplastica e controllo della morte cellulare: p53 The Growth Arrest and DNA Damageinducible 45 (GADD45) proteins have been implicated in regulation of many cellular functions including DNA repair, cell cycle control, senescence and genotoxic stress

14 METASTASI I A tappa Perdita delle giunzioni intercellulari 1) Molecole di adesione intercellulare (adesione omotipica) Caderina E (catenine) Integrine 2) Perdita dell inibizione da contatto 3) Perdita della polarità cellulare Perdita di espresisone di Caderina E promuove epithelial mesenchymal transition (EMT)

15 Ruolo di APC nella regolazione della stabilità e della funzione della β-catenina C-MYC, ciclina D1 Epithelial-mesenchymal transition (EMT) is a program of development of biological cells characterized by loss of cell adhesion, repression of E.cadherin expression, and increased cell mobility

16 Virus oncogeni nell uomo

17 Virus oncogeni e microambiente tumorale

18 Azione di cancerogeni inizianti e promuoventi

19 Tappe nello sviluppo di un carcinoma del colon Molecular model for the evolution of colorectal cancers through the adenoma-carcinoma sequence. Although APC mutation is an early event and loss of p53 occurs late in the process of tumorigenesis, the timing for the other changes may show variations.

20 Selected Oncogenes, Their Mode of Activation, and Associated Human Tumors Category Protooncogene Mode of Activation Associated Human Tumor Growth Factors PDGF-βchain SIS Overexpression Astrocytoma Osteosarcoma Fibroblast growth factors HST-1 INT-2 Overexpression Amplification Stomach cancer Bladder cancer Breast cancer Melanoma TGFα TGFα Overexpression Astrocytomas Hepatocellular carcinomas HGF HGF Overexpression Thyroid cancer Growth Factor Receptors EGF-receptor family ERB-B1 (ECFR) ERB-B2 Overexpression Amplification Squamous cell carcinomas of lung, gliomas Breast and ovarian cancers CSF-1 receptor FMS Point mutation Leukemia Receptor for neurotrophic factors RET Point mutation Multiple endocrine neoplasia 2A and B, familial medullary thyroid carcinomas PDGF receptor PDGF-R Overexpression Gliomas Receptor for stem cell (steel) factor KIT Point mutation Gastrointestinal stromal tumors and other soft tissue tumors Proteins Involved in Signal Transduction GTP-binding K-RAS H-RAS N-RAS Point mutation Point mutation Point mutation Colon, lung, and pancreatic tumors Bladder and kidney tumors Melanomas, hematologic malignancies Nonreceptor tyrosine kinase ABL Translocation Chronic myeloid leukemia Acute lymphoblastic leukemia RAS signal transduction BRAF Point mutation Melanomas WNT signal transduction β-catenin Point mutation Overexpression Hepatoblastomas, hepatocellular carcinoma Nuclear Regulatory Proteins Transcriptional activators C-MYC N-MYC L-MYC Translocation Amplification Amplification Burkitt lymphoma Neuroblastoma, small cell carcinoma of lung Small cell carcinoma of lung Cell-Cycle Regulators Cyclins CYCLIN D CYCLIN E Translocation Amplification Overexpression Mantle cell lymphoma Breast and esophageal cancers Breast cancer Cyclin-dependent kinase CDK4 Amplification or point mutation Glioblastoma, melanoma, sarcoma

21 Oncosoppressori nefroblastoma,

22 Geni caretaker e gatekeeper

23 Geni caretaker e gatekeeper Caretaker Genes: Geni di riparazione Stabilità genomica. Es.: BRCA-1, BRCA-2 Necessari piu eventi gatekeeper Genes: Regolano ingresso In un percorso di oncogenesi es.: RB, p53 Necessario un evento Schematic illustration of the pathways of malignancy initated by mutation of the gatekeeper genes (e.g., APC, NF-1, RB) or caretaker genes (e.g., hmsh2, BRCA-1, BRCA-2)

24 Trasformazione neoplastica e controllo della morte cellulare

25 Effetti delle proteine virali HPV E6 e HPV E7 sul ciclo cellulare papilloma virus umano: papillomi e carcinomi squamosi Effect of HPV proteins E6 and E7 on the cell cycle. E6 and E7 enhance p53 degradation, causing a block in apoptosis and decreased activity of the p21 cell cycle inhibitor. E7 associates with p21 and prevents its inhibition of the Cyclin/CDK4 complex; E7 can bind to RB, removing cell cycle restriction. The net effect of HPV E6 and E7 proteins is to block apoptosis and remove the restrains to cell proliferation

26 Traslocazioni e attivazione di oncogeni Imatinib

27 Sindromi neoplastiche ereditarie