molecular tumor biology 2. - Állatorvostudományi egyetem · molecular tumor biology 2....
Post on 22-May-2020
9 Views
Preview:
TRANSCRIPT
Molecular tumor biology 2.Proto-oncogenes and tumor suppressor genes
Viral factors of the oncogenesis
Dr. Gábor MátisUniversity of Veterinary Medicine
Division of Biochemistry
8 March 2018
Topics
• Overview of regulatory pathways involved inoncogenesis:– Cell cycle– Apoptosis– Signalling pathways – growth, proliferation
• (Proto-)oncogenes and tumor suppressorgenes
• Viral factors of the oncogenesis
The cell cycle
G0 = cells with no more proliferationpotential
G0
G1 = an active cell with normalbiological functions
S = synthesis phase, DNA-replication= duplication of the whole genome.
G2 = production of enzymes,membrane components and cellorganelles
M = mitosis, cell division
Regulation of the cell cycle – cyclins andcyclin-dependent kinases (CDK)
Wikipedia.com;slideplayer.com
The apoptosisApoptosis = programmed cell death• Regulated process• Only the given cell is involved• Requires energy• Catalyzed by the caspase enzymes• Cell organelles are getting fragmented
apoptotic bodies• Physiological, essential process• No inflammation• Apoptosis vs. necrosis!
en.wikipedia.org
The steps and signalling pathways of apoptosis
quora.com
Regulation of growth, replication and transcription:tyrosine kinase dependent pathways
Ras / MAP kinase cascade• 1. Receptor Sos Ras RafMEK
(MAPKK) Erk (MAP kinase) transcription!• 2. MAPK-cascadeRasPI-3-kinasePKB/Akt
http://biokemia.elte.hu/oktatas/bsc/biokemia_jel1.pdf
The Ras / MAP kinase cascade
The role of the Ras / MAP kinase cascade in theoncogenesis
Roberts and Der (2009): Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.Oncogene, 26, 3291-3310.
(Proto-)oncogenes and tumorsuppressor genes – definitions
• Proto-oncogenes:– Involved in the signalling pathways of cell division, cell
growth: stimulatory action– Mutation or increased expression transformed to
oncogenes oncogenesis (tumorigenic transformation)
• Tumor suppressor genes:– Main functions:
• Cell division, DNA replication: inhibitory action• Stimulating cell differentiation• Inducing apoptosis
– Mutation or decreased expression inactivation lackof protective action against cancer
(Proto-)oncogenes
• Growth factors: e.g. PDGF, EGF,IGF-1, VEGF…
• Growth factor receptors:tyrosin kinase type receptors!– e.g. EGF receptor
• Protein kinases• Regulators of cell cycle: cyclins• Anti-apoptotic proteins: e.g. Bcl
family• Transcription factors:
e.g. NF kappa B
Growth factors: the action of PDGF
(Proto-)oncogenes
• Growth factors: e.g. PDGF, EGF, IGF-1,VEGF…
• Growth factor receptors:tyrosin kinase type receptors!– e.g. EGF receptor = EGFR (HER2!)
• Protein kinases• Regulators of cell cycle: cyclins• Anti-apoptotic proteins: e.g. Bcl
family• Transcription factors:
e.g. NF kappa B
Growth factor receptors: the action ofEGFR
mindsofmalady.com
Role of HER2 in the treatment ofmammary gland tumors
Trastuzumab HER2 inhibition
Tyrosine kinase inhibition in thetreatment of canine mastocytoma (2015)
• Imatinib tyrosine kinase (KIT, Bcr-Abl) inhibition
(Proto-)oncogenes
• Growth factors: e.g. PDGF, EGF, IGF-1,VEGF…
• Growth factor receptors:tyrosin kinase type receptors!– e.g. EGF receptor
• Protein kinases: e.g. MAP kinasecascade – Ras, Raf
• Regulators of cell cycle: cyclins• Anti-apoptotic proteins: e.g. Bcl
family• Transcription factors:
e.g. NF kappa B
Protein kinases as proto-oncogenes:Ras, Raf
(Proto-)oncogenes
• Growth factors: e.g. PDGF, EGF,IGF-1, VEGF…
• Growth factor receptors:tyrosin kinase type receptors!– e.g. EGF receptor
• Protein kinases• Regulators of cell cycle: cyclins• Anti-apoptotic proteins: e.g. Bcl
family• Transcription factors:
e.g. NF kappa B
Inhibition of anti-apoptotic proteins
Clinical Cancer Research
The role of Bcl-2 inhibition in thetreatment of tumors
• Taxol/paclitaxel: Bcl-2 inhibition• Mammary gland, ovary-, cervix, GI tumors
(Proto-)oncogenes
• Growth factors: e.g. PDGF, EGF,IGF-1, VEGF…
• Growth factor receptors:tyrosin kinase type receptors!– e.g. EGF receptor
• Protein kinases• Regulators of cell cycle: cyclins• Anti-apoptotic proteins: e.g. Bcl
family• Transcription factors:
e.g. NF kappa B
Effects of NF-kappaB
• Inactive in normal cells, but active in tumorcells!
• Proto-oncogene effect• Stimulation of cell division• Inhibition of apoptosis• Stimulation of angiogenesis (VEGF, IL-8)• Stimulation of metastases
• Other diseases: emergence of asthma, diabetesmellitus, arteriosclerosis!
Dr. Buday László: Orvosi biokémia előadások
Inflammatory processes!
ACTIVATION of NF-kappaB
growth factorreceptor
IKK complex
PI-3-kinase
Ser-32 and Ser-36go throughphosphorylation
Tumor suppressor genes• Cell surface molecules
– TGFβ: stimulating CDK inhibitors• CDK inhibitors: cyclin/cyclin-dependent kinase inhibitors
cell cycle arrest– p16 gene: inactivationmelanoma, pancreas, kidney, lung
tumors– p21 gene
• Citoplasmic signalling molecules: inhibiting the activationof proto-oncogenes– GAP: GTPase-activating proteins activating the GTPase
function of Ras• Transcription factors
– p53 gene: regulation of cell cycle (CDK inhibition!) and apoptosis– Rb (Retinoblastoma) gene: dephosphorylated protein binding
and inactivation of E2F transcription factors• DNS repair genes
The function of TGFβ
Tumor suppressor genes• Cell surface molecules
– TGFβ: stimulating CDK inhibitors• CDK inhibitors: cyclin/cyclin-dependent kinase inhibitors
cell cycle arrest– p16 gene: inactivationmelanoma, pancreas, kidney, lung
tumors– p21 gene
• Citoplasmic signalling molecules: inhibiting the activationof proto-oncogenes– GAP: GTPase-activating proteins activating the GTPase
function of Ras• Transcription factors
– p53 gene: regulation of cell cycle (CDK inhibition!) and apoptosis– Rb (Retinoblastoma) gene: dephosphorylated protein binding
and inactivation of E2F transcription factors• DNS repair genes
The function of p16 and RB proteins
Tumor suppressor genes
• Cell surface molecules– TGFβ: stimulating CDK inhibitors
• CDK inhibitors: cyclin/cyclin-dependent kinase inhibitors cellcycle arrest– p16 gene: inactivationmelanoma, pancreas, kidney, lung tumors– p21 gene
• Citoplasmic signalling molecules: inhibiting the activation of proto-oncogenes– GAP: GTPase-activating proteins activating the GTPase function of
Ras• Transcription factors
– p53 gene: regulation of cell cycle (CDK inhibition!) and apoptosis– Rb (Retinoblastoma) gene: dephosphorylated protein binding and
inactivation of E2F transcription factors• DNS repair genes
The function of p53 protein
• The most important tumor suppressor!! (humantumors: >50% with p53 mutation)
• DNA damage p53 protein detached fromMDM-2 and getting phosphorylated bindingto p21 gene promoter p21 protein production inhibition of cyclin/cyclin-dependent kinasecomplex cell cycle arrest, no proliferation +apoptosis induction
• p53 mutation no protective actiononcogenesis
The function of p53 protein
Seanholton.wordpress.com
Role of p53 in cancer therapy• „Traditional” chemo-/radiotherapy: DNA damage activation of p53
• Removal of mutant p53: Adenoviruses (E1B-deleted) replicating only in p53-mutant tumorcells
• Insertion of wild-type p53:– Gene therapy with Retrovirus vector (lung tumors)– Gene therapy with Adenovirus vector (Ad-p53)
(ovarian tumors) – Gendicine (Advexin)• Activating p53 signalling
Tumor suppressor genes• Cell surface molecules
– TGFβ: stimulating CDK inhibitors• CDK inhibitors: cyclin/cyclin-dependent kinase inhibitors
cell cycle arrest– p16 gene: inactivationmelanoma, pancreas, kidney, lung
tumors– p21 gene
• Citoplasmic signalling molecules: inhibiting the activationof proto-oncogenes– GAP: GTPase-activating proteins activating the GTPase
function of Ras• Transcription factors
– p53 gene: regulation of cell cycle (CDK inhibition!) and apoptosis– Rb (Retinoblastoma) gene: dephosphorylated protein binding
and inactivation of E2F transcription factors• DNS repair genes
The function of GAP
Proto-oncogenes and tumor suppressor genes
top related