SIGNALING PATHWAYS SIGNALING PATHWAYS IN CANCER .IN CANCER .

BYP.B.Tirupathi Pichiah

1st Year Master of Science in Animal Biotechnology.Dept of Animal Science.

Bharathidasan University, Trichy.

CHAPTER 5

TOPICS TO BE DISCUSSEDTOPICS TO BE DISCUSSED1.1. RAS-RAF-MAP kinase pathway.RAS-RAF-MAP kinase pathway.

2.2. Phospotidylinositol-3 kinase signaling pathway.Phospotidylinositol-3 kinase signaling pathway.

3.3. mTORmTOR

4.4. Translation control and growth.Translation control and growth.

5.5. Cytokine signalingCytokine signaling

6.6. JAK / STAT pathwaysJAK / STAT pathways

7.7. Growth signaling via cell adhesion- the Wnt-Growth signaling via cell adhesion- the Wnt-ββ-catenin pathway.-catenin pathway.

8.8. Notch signalingNotch signaling

9.9. NUCLEAR PROTO-ONCOGENES AND TRANSCRIPTION FACTORS.NUCLEAR PROTO-ONCOGENES AND TRANSCRIPTION FACTORS.

RAS-RAF-MAP kinase pathway.RAS-RAF-MAP kinase pathway. RAF is the first member of three-kinase modular sequence, with RAF is the first member of three-kinase modular sequence, with

generic designation MAPKKK,MAPKK,MAPK.generic designation MAPKKK,MAPKK,MAPK.

MAPK-Mitogen Activated Protein Kinase.MAPK-Mitogen Activated Protein Kinase.

More than 6 distinct pathway follow this general pattern in mammalian More than 6 distinct pathway follow this general pattern in mammalian cells including JUN kinase/stress activated kinase (SAPK)cells including JUN kinase/stress activated kinase (SAPK)

The mitogenic pathway involves RAF, MAPK/ERK kinase (MEK1 and The mitogenic pathway involves RAF, MAPK/ERK kinase (MEK1 and 2) and extracellular receptor kinase (ERK1 and 2).2) and extracellular receptor kinase (ERK1 and 2).

Sequential kinase cascades may function to amplify the input signal.Sequential kinase cascades may function to amplify the input signal.

Linking of some scaffold proteins such as MP1 (MEK Partner) and JIP1 Linking of some scaffold proteins such as MP1 (MEK Partner) and JIP1 (JUN N-terminal kinase interacting protein) prevents signal (JUN N-terminal kinase interacting protein) prevents signal amplification.amplification.

Prevents undesirable spread of signaling across multiple pathway.Prevents undesirable spread of signaling across multiple pathway.

The end result of MAPK sequence is relocation of active ERK to the The end result of MAPK sequence is relocation of active ERK to the nucleus , and phosphorylation of regulated transcription factors of the ETS nucleus , and phosphorylation of regulated transcription factors of the ETS family.family.

Ultimately this lead to enhanced expression of other key transcription Ultimately this lead to enhanced expression of other key transcription factors such as c-MYC, which is key to cell cycle control. factors such as c-MYC, which is key to cell cycle control.

RAS-RAF-MAP kinase pathway.RAS-RAF-MAP kinase pathway.

RTK(e.g. IGF)

PLCγ PDK1 IRS PI3kp85

(SH2 domain)

PI3kp110

(catalytic subunit)

PDK1

PTEN

GSK3β FOXO

AKT

p21K1P1 , p21CIP1

Induction of genes for cellular

replication, growth and apoptosis

suppression

e1F4E

4EBP1

S6K1

TSC1TSC2

4EBP1

MTOR

RHEB

TSC2 TSC1

AMPK AMPK

APOPTOSIS S6K1

AKT

BAD PAR-4 IKK

NFкB

LKB1 PKC

P

P

P

P

P

P

P

PIP3

PIP2

PIP2DAG

LIGAND

Fig. 5.17Lipid signaling from receptor tyrosine kinase (such as IGF-IR, HER2/Neu,VEGF-R,PDGF-R)

Phosphatidylinositol-3 kinase Phosphatidylinositol-3 kinase signaling pathway.signaling pathway.

Phosphatidylinositol-3 kinase (PI3K) signaling pathway is as important as Phosphatidylinositol-3 kinase (PI3K) signaling pathway is as important as theRAS-MAP kinase pathway in cell survival and proliferation.theRAS-MAP kinase pathway in cell survival and proliferation.

PI3K constitute lipid kinase family characterized by their ability to phosporylate PI3K constitute lipid kinase family characterized by their ability to phosporylate inositol 3’-OH group in inositol phospholipids to generate the second messenger inositol 3’-OH group in inositol phospholipids to generate the second messenger Phosphatidylinositol-3,4,5-triphosphate (PIP-3)Phosphatidylinositol-3,4,5-triphosphate (PIP-3)

PIP-3 activates down stream kinases – AKT / PKB and S6K.PIP-3 activates down stream kinases – AKT / PKB and S6K.

PIP-3 activates the serine / threonine kinase AKT by promoting translocation to PIP-3 activates the serine / threonine kinase AKT by promoting translocation to the inner membrane where it is Phosporylated and activated by PDK1 and PDK2.the inner membrane where it is Phosporylated and activated by PDK1 and PDK2.

Then in turn ATK activates numerous substrate in regulation of cell survival, cell Then in turn ATK activates numerous substrate in regulation of cell survival, cell cycle progression and cellular growth, including NF-kappa B, mTOR (and thence cycle progression and cellular growth, including NF-kappa B, mTOR (and thence S6K),S6K),Forkhead,BAD,GSK3Forkhead,BAD,GSK3ββ, and MDM2., and MDM2.

Growth factors such as insulin and IGFs can activated PI3K-AKT pathway via Growth factors such as insulin and IGFs can activated PI3K-AKT pathway via the IRS-2 adaptor protein recruited to activate RTK.(imp in beta cell growth the IRS-2 adaptor protein recruited to activate RTK.(imp in beta cell growth regulation) regulation)

Deregulation of PI3K- CANCER due to loss of the Tumor Supressor Protein Deregulation of PI3K- CANCER due to loss of the Tumor Supressor Protein PTEN (Phosphate and tensin homolog)PTEN (Phosphate and tensin homolog)

Also may lead to cytoskelton deformability and motility.Also may lead to cytoskelton deformability and motility.

AKT is hyper activated in Human cancer.AKT is hyper activated in Human cancer.

AKT activation is regulated by two tumor suppressors, PTEN and TSC1/TSC2AKT activation is regulated by two tumor suppressors, PTEN and TSC1/TSC2

PTEN = Breaks PIP-3 to PIP2 = inhibit PI3K upstream of AKT.PTEN = Breaks PIP-3 to PIP2 = inhibit PI3K upstream of AKT.

Phosphatidylinositol-3 kinase Phosphatidylinositol-3 kinase signaling pathway.signaling pathway.

TSC1/TSC2 = Heterodimer = acts on downstream of AKT & upstream of TSC1/TSC2 = Heterodimer = acts on downstream of AKT & upstream of mTOR.mTOR.

PTEN & PTEN & p53 p53 tumor suppressors are among the most comonly inactivated tumor suppressors are among the most comonly inactivated or mutated gene in human cancer.or mutated gene in human cancer.

Inactivation of PTEN = Growth arrest through the Inactivation of PTEN = Growth arrest through the p53 p53 dependent cellular dependent cellular senesence pathway both senesence pathway both in vitro in vitro and and in vivoin vivo..

Activation of the PI3K – AKT pathway renders cancer cells resistant to Activation of the PI3K – AKT pathway renders cancer cells resistant to apoptotic signals and promote tumor growth.apoptotic signals and promote tumor growth.

Phosphatidylinositol-3 kinase Phosphatidylinositol-3 kinase signaling pathway.signaling pathway.

Inhibition of GSK3Inhibition of GSK3ββ is one important contributor as is phosphorylation of is one important contributor as is phosphorylation of BAD.BAD.

Recent studies suggest that AKT may prevent apoptosis in some cases by Recent studies suggest that AKT may prevent apoptosis in some cases by phosphorylation of proapoptotic protein, PAR-4.phosphorylation of proapoptotic protein, PAR-4.

Suppressing AKT activation by PTEN cause apoptosis in cancer cells.Suppressing AKT activation by PTEN cause apoptosis in cancer cells.(Goswami et al ).(Goswami et al ).

Apoptosis resulting from inhibition of AKT was blocked by inhibition of Apoptosis resulting from inhibition of AKT was blocked by inhibition of other apoptosis agonist that are AKT substrate.other apoptosis agonist that are AKT substrate.

Phosphatidylinositol-3 kinase Phosphatidylinositol-3 kinase signaling pathway.signaling pathway.

mTOR.mTOR. mTORmTOR = = mmammalian ammalian TTarget arget OOf f RRapamycin protein.apamycin protein.

downstream effector of the PI3K / AKT signaling.downstream effector of the PI3K / AKT signaling.

mTOR is known to be involved in key cellular processes such as cell size, mTOR is known to be involved in key cellular processes such as cell size, survival, and proliferation. (membrane trafficking, protein degradation, survival, and proliferation. (membrane trafficking, protein degradation, protein kinase C signaling, ribosome biogenesis and transcription, activates protein kinase C signaling, ribosome biogenesis and transcription, activates 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1 ( EIF4E).factor 4E-binding protein 1 ( EIF4E).

Survival signals generated by PI3K and phospholipase D target mTOR, Survival signals generated by PI3K and phospholipase D target mTOR, which in turn contributes to supression of apoptotic pathways in cancer which in turn contributes to supression of apoptotic pathways in cancer cells.cells.

mTOR prevent mTOR prevent GG1 1 / S/ S transition by non spesific inhibition of cell growth and also transition by non spesific inhibition of cell growth and also preventing CDK activation.preventing CDK activation.

HAMARTOMAS HAMARTOMAS :- Autosomal dominant, Germline mutation of :- Autosomal dominant, Germline mutation of TSC1TSC1 or or TSC2TSC2, , tumor development. tumor development.

TSC1 = TSC1 = hamartin and hamartin and TSCTSC2 = tuberin. ( both responsible for regulation of 2 = tuberin. ( both responsible for regulation of Cell and Organ size )Cell and Organ size )

PI3 AKT mTOR S6KPI3 AKT mTOR S6K

ATK phosphorylates TSC2 in TSC1 / TSC2 protein complex inactivating it. While ATK phosphorylates TSC2 in TSC1 / TSC2 protein complex inactivating it. While TSC1 / TSC2 has GAP activity for RHEB and activated RHEB-GTP activates mTOR.TSC1 / TSC2 has GAP activity for RHEB and activated RHEB-GTP activates mTOR.

Cell lacking TSC1 or TSC2 there is are increased levels of RHEB-GTP, which leads to Cell lacking TSC1 or TSC2 there is are increased levels of RHEB-GTP, which leads to activation of mTOR, leading to cell size increase and growth.activation of mTOR, leading to cell size increase and growth.

mTOR.mTOR.

Translation control and growthTranslation control and growth Cell proliferation needs general increase protein synthesis and a specific increase Cell proliferation needs general increase protein synthesis and a specific increase

in the synthesis of replication-promoting proteins.in the synthesis of replication-promoting proteins.

RAS-MAPK-and PI3K-AKT-mTOR pathways are particular.RAS-MAPK-and PI3K-AKT-mTOR pathways are particular.

Translation Translation eIFeIF Ribosomal Subunit + mRNA . Ribosomal Subunit + mRNA .eIF4 = eIF4E, eIF4G, eIF4A, eIF4B.eIF4 = eIF4E, eIF4G, eIF4A, eIF4B.

Polypeptide chain initiation involves the assembly of 43S initiation complex Polypeptide chain initiation involves the assembly of 43S initiation complex catalyze by polypeptidechain initiation factor eIF2 and the binding of eIF4E to catalyze by polypeptidechain initiation factor eIF2 and the binding of eIF4E to eIF4G during the recruitment of mRNA to the ribosome.eIF4G during the recruitment of mRNA to the ribosome.

eIF2 activity is controlled by phosphorylation of the alpha subunit done by various eIF2 activity is controlled by phosphorylation of the alpha subunit done by various kinases (GCN2, and eIF2 alpha kinase 4)kinases (GCN2, and eIF2 alpha kinase 4)

Different eIF4 protein promote or inhibit translation of specific mRNAs.Different eIF4 protein promote or inhibit translation of specific mRNAs.

mTOR – by S6K and eIF4E.mTOR – by S6K and eIF4E.

Deregulation of gene expression at the level of mRNA translation can Deregulation of gene expression at the level of mRNA translation can contribute to cell transformation and the malignant phenotype.contribute to cell transformation and the malignant phenotype.

eIF4E cooperate with c-MYC in B-cell lymphomagenesis ; in this case c-eIF4E cooperate with c-MYC in B-cell lymphomagenesis ; in this case c-MYC could overcome growth arrest triggered by deregulated eIF4E and MYC could overcome growth arrest triggered by deregulated eIF4E and eIF4E could prevent c-MYC dependent apoptosis.eIF4E could prevent c-MYC dependent apoptosis.

eIF4E over expression – head & neck, prostrate, Breast, Overian, bladder, eIF4E over expression – head & neck, prostrate, Breast, Overian, bladder, lung cancer.lung cancer.

Translation control and growthTranslation control and growth

eIF4E regulates the requirement of mRNA to ribosome and thereby eIF4E regulates the requirement of mRNA to ribosome and thereby regulates cap-dependent protein synthesis, eIF4E also selectively enables regulates cap-dependent protein synthesis, eIF4E also selectively enables translation of a select number of directly cancer relevent mRNAs, such as translation of a select number of directly cancer relevent mRNAs, such as those encoding cyclin D1, c-MYC, MMP-9, and VEGF.those encoding cyclin D1, c-MYC, MMP-9, and VEGF.

eIF2 and various regulatory kinase play key role in regulation of protein eIF2 and various regulatory kinase play key role in regulation of protein synthesis in respond to stresses. Phosphorylation of eFI2 reduces general synthesis in respond to stresses. Phosphorylation of eFI2 reduces general protein synthesis, but increases the translation of specific mRNA that protein synthesis, but increases the translation of specific mRNA that codes transcripton factors.codes transcripton factors.

Translation control and growthTranslation control and growth

Cytokine Signaling.Cytokine Signaling. Cytokines and growth factors activates the MAP kinase pathway resulting Cytokines and growth factors activates the MAP kinase pathway resulting

in the stimulation of ERK1 / 2, c-Jun N-terminal kinases, and p38 kinase, in the stimulation of ERK1 / 2, c-Jun N-terminal kinases, and p38 kinase, which in turn activate transcription factors like AP-1 and AP-2.which in turn activate transcription factors like AP-1 and AP-2.

Pro-inflammatory agents such as TNF-Pro-inflammatory agents such as TNF-αα and IL-1 can activate the and IL-1 can activate the transcription factor NF-transcription factor NF-ккB that in turn regulate the expression of B that in turn regulate the expression of immediately early genes involve in the immune acute phase and in immediately early genes involve in the immune acute phase and in inflammatory responses.inflammatory responses.

NF-NF-ккB and AP-1 are immediate-early transcriptional activators, component B and AP-1 are immediate-early transcriptional activators, component of the JAK / STAT pathway play an important role in the transcriptional of the JAK / STAT pathway play an important role in the transcriptional activation of many inflammatory genes.activation of many inflammatory genes.

JAK / STAT pathwaysJAK / STAT pathways JAK-STAT pathway comprises 3 families of proteins.JAK-STAT pathway comprises 3 families of proteins.1.1. JaJanus nus kkinases (JAK) inases (JAK) 2.2. SSignal ignal TTransducers and ransducers and AActivators of ctivators of TTranscription (STAT)ranscription (STAT)3.3. Their endogenous inhibitor SOCS family. Their endogenous inhibitor SOCS family.

JAK-STAT pathway is utilized by various cytokines and growth factors.JAK-STAT pathway is utilized by various cytokines and growth factors.

Defective JAK-STAT-SOCS pathway may impair tumour responses to Defective JAK-STAT-SOCS pathway may impair tumour responses to immunotherapy.immunotherapy.

This pathway controls cell growth, cell differentiation , senescence, and This pathway controls cell growth, cell differentiation , senescence, and apoptosis.apoptosis.

JAK / STAT pathwaysJAK / STAT pathways STAT- family proteins are latent cytoplasmic transcription factor that STAT- family proteins are latent cytoplasmic transcription factor that

convey signals from cytokine and growth factor receptors to the nucleus.convey signals from cytokine and growth factor receptors to the nucleus.

Binding of cytokine to cell surface receptor results in two categories of Binding of cytokine to cell surface receptor results in two categories of signaling..signaling..

1.1. Activation of Cytoplasmic Tyrosine Kinase ( JAK or SRC Activation of Cytoplasmic Tyrosine Kinase ( JAK or SRC kinase family )kinase family )

2.2. Receptor intrinsic tyrosine kinase activity (PDGF, EGF) Receptor intrinsic tyrosine kinase activity (PDGF, EGF) Tyrosine +P = activates STAT monomer = dimerize thrrough interaction Tyrosine +P = activates STAT monomer = dimerize thrrough interaction

of SH2 domains. (SRC homology 2)of SH2 domains. (SRC homology 2) Resultant STAT dimer translocate to STAT specific site known as Resultant STAT dimer translocate to STAT specific site known as

gamma – activated sites (GAS) of target gene to induce transcription.gamma – activated sites (GAS) of target gene to induce transcription.

JAK / STAT pathwaysJAK / STAT pathways STAT proteins especially STAT3 and STAT5 regulate the apoptosis STAT proteins especially STAT3 and STAT5 regulate the apoptosis

resistant, angiogenesis and evade immune surveillance in tumor cells.resistant, angiogenesis and evade immune surveillance in tumor cells.

Epigenetic silencing of the SOCS-1 gene, an inhibitor of JAK/STAT Epigenetic silencing of the SOCS-1 gene, an inhibitor of JAK/STAT pathway, has been described in liver cancer.pathway, has been described in liver cancer.

Constitutive activation of the JAK/STAT pathway is known to occur in Constitutive activation of the JAK/STAT pathway is known to occur in HTLV-I-transformed T cells, Sezary’s syndrome, and v-HTLV-I-transformed T cells, Sezary’s syndrome, and v-ablabl or v- or v-src src transformation.transformation.

STAT3 and 5, most frequently observed in cancers (head, neck, lung, STAT3 and 5, most frequently observed in cancers (head, neck, lung, kidney,prostrate, breast, ovarian and blood)kidney,prostrate, breast, ovarian and blood)

JAK / STAT pathwaysJAK / STAT pathways Aberrant signaling through a number of upstream pathways can result in Aberrant signaling through a number of upstream pathways can result in

constitutively activated STAT in tumor cells.constitutively activated STAT in tumor cells.

cellular transformation with v-src or BCR-ABL activates STAT3 and STAT5 cellular transformation with v-src or BCR-ABL activates STAT3 and STAT5 and constitutively active STAT3 will transform immortalized fibroblast.and constitutively active STAT3 will transform immortalized fibroblast.

STAT5 can control transcription of various factors implicated in cancer STAT5 can control transcription of various factors implicated in cancer including BCL-Xincluding BCL-XL L , PIM-1, and cyclin D1 suggesting a role both in resistant to , PIM-1, and cyclin D1 suggesting a role both in resistant to apoptosis and replication .apoptosis and replication .

JAK tyrosine kinase are activated by interleukin and other growth factors, and JAK tyrosine kinase are activated by interleukin and other growth factors, and promote survival and proliferation of cell in multiple tissue and are promote survival and proliferation of cell in multiple tissue and are constitutively active in many hematopoitic malignancies and certain carcinoma.constitutively active in many hematopoitic malignancies and certain carcinoma.

JAK / STAT pathwaysJAK / STAT pathways JAK can activates both STAT and PI3K signaling.JAK can activates both STAT and PI3K signaling.

JAK activity is essential for lymphoma invasion and metastasis, JAK activity is essential for lymphoma invasion and metastasis, independent of its role in survival and proliferation, and independent of independent of its role in survival and proliferation, and independent of STAT and PI3 signaling.STAT and PI3 signaling.

Therapy targeting JAK-STAT pathway – tryphostin (AG 490), a JAK Therapy targeting JAK-STAT pathway – tryphostin (AG 490), a JAK protein kinase inhibitor ,and sant 7, an IL-6 receptor antagonist.protein kinase inhibitor ,and sant 7, an IL-6 receptor antagonist.

INFα

Cytokine receptor( interferon α receptor)

autophosphorylation of JAK

Receptor phosphorylation INFαR Dimer

Docking of STAT and their phosphorylation

DNA respond element

JAK- STAT PATHWAY

dimerization

Growth signaling via cell adhesion-Growth signaling via cell adhesion-the Wnt-the Wnt-ββ-catenin pathway.-catenin pathway.

Cell-cell adhesiveness is decreased in cancer, enabling deregulated Cell-cell adhesiveness is decreased in cancer, enabling deregulated proliferation, migration, invasion and metastases, but in general only if proliferation, migration, invasion and metastases, but in general only if cells can survive loss of cell-cell contacts.cells can survive loss of cell-cell contacts.

E-caderin and interacting catenins = connects cadherin to cytoskelton.E-caderin and interacting catenins = connects cadherin to cytoskelton.

silencing of E-caderin gene by DNA hypermethylation frequent in silencing of E-caderin gene by DNA hypermethylation frequent in precancerous condition.precancerous condition.

ββ-catenin also connects the E-catenin to Wingless/Wnt signaling pathway.-catenin also connects the E-catenin to Wingless/Wnt signaling pathway.

Specification and localization of new cells.Specification and localization of new cells.

Growth signaling via cell adhesion-Growth signaling via cell adhesion-the Wnt-the Wnt-ββ-catenin pathway.-catenin pathway.

Wnt ligand binds to “Frizzled” membrane receptor and interfere with the multi-Wnt ligand binds to “Frizzled” membrane receptor and interfere with the multi-protein destruction complex, resulting in down stream activation of gene protein destruction complex, resulting in down stream activation of gene transcription by transcription by ββ-catenin.-catenin.

multi-protein destruction complex require presence of Axin +APC (Adenomatosis multi-protein destruction complex require presence of Axin +APC (Adenomatosis polyposis coli ) acts as scaffolds to facillate phosphorylation of beta-catenin by polyposis coli ) acts as scaffolds to facillate phosphorylation of beta-catenin by enzyme GSK3enzyme GSK3ββ..

P P PROTEOSOMEPROTEOSOME

++ nuclear transcription factor = expression of nuclear transcription factor = expression of

cMYC,cJUN,Fra,Cyclin D1 cMYC,cJUN,Fra,Cyclin D1

ββ-catenin-catenin

ββ-catenin-catenin

Dishevelled

AXIN

APCAXIN APC

GSK3 β-Catenin

Degradation in the proteosome

β cateninTCF

c-MYC, cyclin D

GSK3

GPP

Frizzled

Notch signaling.Notch signaling. Drosophila – notch wings –Thomas Hunt (Morgan Lab 1910)Drosophila – notch wings –Thomas Hunt (Morgan Lab 1910) Ligand protein is Delta.Ligand protein is Delta. Juxtracrtine interaction.Juxtracrtine interaction. Mammals – ligands Delta like 1,-3,-4 and Jagged -1 and -2. Mammals – ligands Delta like 1,-3,-4 and Jagged -1 and -2.

Family of four receptors (Notch 1,-2,-3 and 4)Family of four receptors (Notch 1,-2,-3 and 4)

• PEST sequence regulates protein stability.

•Following the ligand binding:-•Removal of ligand binding domain by metalloproteinase enzyme TACE.•Release of cytoplasmic domain (ic Notch) by secretase & presenillin.

Gene expression in turn activated by ic Notch in part of binding to Gene expression in turn activated by ic Notch in part of binding to ubiqutitous CSL transcriptional repressor.ubiqutitous CSL transcriptional repressor.

ic Notch + CSL ic Notch + CSL recruit other proteins including master mind like recruit other proteins including master mind like protein.+ Transcription factors Hairy/ protein.+ Transcription factors Hairy/ enhancer of enhancer of Split (HES) family + Cell cycle & Split (HES) family + Cell cycle & apoptosis.apoptosis.

Cell fate depends on cell to cell communication – ic Notch signaling.Cell fate depends on cell to cell communication – ic Notch signaling. Important in embryonic development.Important in embryonic development. T-ALL = T-cell acute lymbhoblastic leukemia.- recurrent chromosomal T-ALL = T-cell acute lymbhoblastic leukemia.- recurrent chromosomal

translocation involving Notch gene and T-cell receptor translocation involving Notch gene and T-cell receptor ββ activates the ic activates the ic Notch independent to ligand and it is regulated by TCRNotch independent to ligand and it is regulated by TCRββ..

Notch signaling.Notch signaling.

Deregulation of ic Notch Deregulation of ic Notch lymphoid development in expense of B-cell lymphoid development in expense of B-cell and by preventing full T-cell diffrentiation.and by preventing full T-cell diffrentiation.

Notch is also involve in mouse mammary tumor virus (MMTV) induced Notch is also involve in mouse mammary tumor virus (MMTV) induced breast cancer.breast cancer.

Notch inhibitor is NUMB or Deltex.Notch inhibitor is NUMB or Deltex. Inactive NUMB are seen in breast cancer.Inactive NUMB are seen in breast cancer. Nedd4 is a ubiqutin ligase it activate Notch signal independent of Ligand.Nedd4 is a ubiqutin ligase it activate Notch signal independent of Ligand. Nedd4 and Deltex commpete to regulate Notch signaling.Nedd4 and Deltex commpete to regulate Notch signaling. Notch signaling could be manipulated in cancer by targeting of the Notch signaling could be manipulated in cancer by targeting of the

ubiqutin proteosome pathway ubiqutin proteosome pathway

Notch signaling.Notch signaling.

NUCLEAR PROTO- ONCOGENES NUCLEAR PROTO- ONCOGENES AND TRANSCRIPTION FACTORS.AND TRANSCRIPTION FACTORS.

Ultimately signals from growth factor receptor signaling pathways control Ultimately signals from growth factor receptor signaling pathways control growth by regulating gene expression in the nucleus.growth by regulating gene expression in the nucleus.

Thus ERK and STAT can enter the nucleus, where they in turn activate the Thus ERK and STAT can enter the nucleus, where they in turn activate the proto oncogenes c-MYC, c-FOS and c-JUN.proto oncogenes c-MYC, c-FOS and c-JUN.

JUN protein, the target of the JNK signaling pathway, is constitutive JUN protein, the target of the JNK signaling pathway, is constitutive transcription factor that regulates survival but is only a week regulator of transcription factor that regulates survival but is only a week regulator of proliferation as homodimer.proliferation as homodimer.

JUN+FOS (Finkel Osteosarcoma) product of c-MYC=induce JUN+FOS (Finkel Osteosarcoma) product of c-MYC=induce transcription= gives heterodimer = activates genes with tumor respond transcription= gives heterodimer = activates genes with tumor respond element enhancer.element enhancer.

JUN/FOS hetrodymer regulate gene involved in cell growth and may result JUN/FOS hetrodymer regulate gene involved in cell growth and may result in loss of diffrentiation.in loss of diffrentiation.