3 - Kearns - Signal Transduction

Which are the following general steps in signal transduction? SATA

a. reception

b. transduction

c. translation

d. response

a, b, d (reception—> transduction—> response)

In tumor growth, what can happen to the general steps in the signal transduction pathway? SATA

a. the signaling molecule becomes deactivated

b. cell proliferation

c. increase in tumor suppressor genes

d. decrease in oncogene transcription

a, b (DECREASE in tumor suppressor genes, INCREASE in oncogenes)

What are some examples of signaling pathways that cancer uses to grow?

(don’t memorize just here for a summary)

• transcription factor activation

• angiogenesis

• TF NF-kB

• UPP

• mTOR

• tumor suppressor genes

How does activating transcription factors lead to cell growth/proliferation?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	binding of a ligand
signal reception	ligand binding domain
signal transduction	activated tyrosine kinase and intracellular target transcription factor by phosphorylation gene expression is regulated
cellular response	CELL GROWTH/PROLIFERATION

Summary—> ligand binds to binding domain —→ PHOSPHORYLATION OF TYROSINE KINASE—> activate intracellular TFs—> increase in cell growth

What do tyrosine kinase inhibitors do to cancer cells? What is their cytoplasmic and nuclear MOA?

• tyrosine kinase inhibitors INHIBIT CELL GROWTH, proliferation, differentiation, and metabolic regulation

• Cytoplasmic MOA- block phosphorylation of tyrosine kinase and other kinases

• Nuclear MOA- inhibits gene transcription

Which of the following would a tyrosine kinase inhibitor inhibit?

a. DNA replication

b. protein synthesis

c. both

c

How does the process of angiogenesis work?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	VGEF
signal reception	VEGFRs dimerize (cell surface tyrosine kinase receptors)
signal transduction	phosphorylation activates the receptors Ras/MAP pathway + others are activated increase in VEGF transcription/translation
cellular response	building new blood vessels increases cell growth, migration, and metastasize

What does VEGF stand for?

vascular endothelial growth factor

oncogenes lead to ________ in cancer cells.

a. growth

b. death

c. angiogenesis

d. all of the above

a

What are 4 examples of oncogenes? (these are the ones kearns said to know)

• EGFR

• HER2

• c-MYC

• BCR-ABL

What is the following function of each oncogene:

• EGFR

• HER2

• c-MYC

• BCR-ABL

• EGFR: genes for growth factors or their receptors -codes for epidermal growth factor receptor

• HER2: genes for growth factors or their receptors- codes for growth factor receptor

• c-MYC: genes for transcription factors that activate growth-promoting genes

• BCR-ABL: genes for cytoplasmic kinases- codes for nonreceptor tyrosine kinase

The Philadelphia chromosome (a BCR-ABL oncogene) is an example of how an oncogene can become functional. Explain how this gene becomes functional. (not that important)

• basically there are 2 genes on 2 normal chromosomes (ABL gene on chromosome 9 and BCR gene on chromosome 22)

• during replication, epigenetic factor, etc. SOMETHING HAPPENS and the chromosomes break

• when the chromosomes break off they don’t reattach to the same place and instead the 2 broken pieces come together

• this makes the BCR-ABL oncogene ❤

think: BCR and ABL are protooncogenes and when they come together = oncogene

How does TF NF-kB cause cell proliferation in cancer?

• What is the role of NF-kB?

• What is the signal transduction pathway?

• What is the cellular response?

• role- protein that control many cell fxns (proliferation, metastasis, inflammation, angiogenesis, survival)

• signal transduction

  • regulation of cyclin D1 and C-MYC

• response- cell proliferation and promotes tumor growth

What are the pros and cons of NF-kB on TUMOR GROWTH?

• pros

  • regulate expression of cyclin D1 and C-MYC

  • response- increase tumor cell proliferation, survival, and metastasis

• cons

  • acts as tumor suppressor in keratinocytes—> rashes/dryness

  • response- increased risk of squamous cell carcinoma

What is the Ubiquitin Proteasome pathway responsible for?

intracellular protein degradation in all cells

Ubiquitin signals the protein for degradation by the _________________.

proteosome

Do cancer cells want to be ubiquinated?

no

How does the process of proteosome inhibition work?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	cytokines
signal reception	cytokine binding cell surface receptors
signal transduction	inhibit transcription factors p50 and p65 increase NF-kB translocation to the nucleus to act
cellular response	decrease cell proliferation

How does the process of the MTOR signaling pathway work?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	cytokines
signal reception	cytokine binding cell surface receptors
signal transduction	cytokine response is inhibited IL-2 inhibited cell cycle progression inhibited
cellular response	decrease cell proliferation

What are some examples of tumor suppresor genes? (the ones kearns wants us to know)

• NF-1

• NF-2

• RB1

• p53

• BRCA1

• BRCA2

What type of genes are NF-1 and NF-2 and what is their function?

• type of gene- genes for proteins in the cytoplasm

• function- codes for protein that inhibits stimulatory Ras protein

What type of genes are RB1 and p53 and what is their function?

• type of gene- for proteins in the nucleus

• function:

  • RB1- code for pRB protein, master brake of the cell cycle

  • p53- codes for p53 protein, which can halt cell division and induce apotosis

What type of genes are BRCA1 and BRCA2 and what is their function?

• type of gene- genes for proteins whose cellular location is unclear

• function- DNA repair and transcriptional regulation

How does a mutation in p53 lead to cell growth?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	DNA damage, oncogene activation, hypoxia, telomere erosion
signal reception	various cell surface receptors
signal transduction	phosphorylation by kinase enzymes conformation change of p53 protein nuclear translocation of the TF p53 responsive element
cellular response	DNA repair, tumor suppressor activity, cell growth

What are some ways a cancer cell can evade cell death? (don’t memorize just for summary)

• TNF

• PD-L1

• CTLA4

Tumor Necrosis Factor is a cytokine that signals _______________ which signals ____________________.

Tumor Necrosis Factor is a cytokine that signals INFLAMMATION which signals the immune system to cause tumors to “die from the inside out” aka necrosis..

How does a mutation in TNFs cause the cancer cell to survive apoptosis?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	TNF
signal reception	TNF receptor
signal transduction	phosphorylation NF-kB activation p38 activation (tumor suppressor gene)
cellular response	cell survival

How does a mutation in PD-L1 (an immune checkpoint) cause the cancer cell to survive apoptosis?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	PD-1 receptor on the T cell
signal reception	PD-L1 (receptor on target cell)
signal transduction	t cell migration to the tumor
cellular response	decreased cell death in the tumor turns “off” the t-cell immune response to “kill”

How does a mutation in CTLA4 (an immune checkpoint) cause the cancer cell to survive apoptosis?

• what is the signaling molecule?

• what is the signal reception?

• what is the signal transduction?

• what is the cellular response?

signaling molecule	signals on antigen presenting cell
signal reception	naive T cells
signal transduction	antigen presenting cell—> migration to lymph node—> t cell recruitment—> t cell expresses CTLA4 receptor—> T cell migrates to tumor—> “turns on PD1”
cellular response	decreased cell death in the tumor turns “off” the t-cell immune response to “kill”

An important part of apoptosis is activating __________.

capsases