BIO 19

addition of serum to quiescent ___ yields a marked ___ in the activity of two ___, ____ and ____

1) 3T3 cells 2) increase 3) proto-oncogene products 4) c-fos 5) c-myc

activating mutations in ___ occur in ___ melanomas

1) B-Raf gene 2) 40%

____ is a BRC-ABL inhibitor that inhibits ___ activity; it is successful in the treatment of chronic leukemia

1) Imatinib (Gleveec) 2) ABL kinase

what pathway does a mutation in MLH1 and other DNA mismatch repair genes affect?

DNA mismatch repair

who binds once RTK is activated?

GRB2

what pathway does a mutation in K-Ras affect?

RTK signaling

ras^V12

an oncoprotein

what is the inactive form of Raf?

(an N-term regulatory domain and a C-term kinase domain) with a phosphate on each domain, both capped by 14-3-3 cap

what is the active form of Raf?

(an N-term regulatory domain and a C-term kinase domain) with its 3 (C-term only!!) phosphates exposed; activated by active Ras

adenoma

(epithelial BENIGN tumor): neoplastic gland tubules enclosed by fibrous connective tissue capsule of benign tumor. normal gland tubules outside the capsule

activation of a proto-oncogene to an oncogene: gene amplification

*gene shows up more in dna **NORMAL protein greatly OVERPRODUCED

activation of a proto-oncogene to an oncogene: deletion or point mutation in coding sequence

*problem in dna sequence, which is of course transcribed into an rna sequence problem **results in HYPERACTIVE protein made in NORMAL amounts

activation of a proto-oncogene to an oncogene: regulatory mutation

*problem in regulation of transcription **NORMAL protein greatly OVERPRODUCED

what does GRB2 look like?

1 SH2 domain and 2 SH3 domains

the MAP kinase pathway activated by Ras

1) Ras activated by exchange of GDP for GTP 2) active Ras recruits, binds, and activates Raf 3) GTP hydrolysis leads to dissociation of Ras from Raf 4) Raf activates MEK (using ATP hydrolysis) 5) MEK activates MAPK (using ATP hydrolysis) 6) dimeric form of active MAP kinase translocates to nucleus; activates many transcription factors

what are the stages of tumor growth in colon cancer?

1) a polyp (small growth) forms on the colon wall 2) a benign, precancerous tumor grows 3) a class II adenoma (benign) grows 4) a class III adenoma (benign) grows 5) a malignant carcinoma develops 6) the cancer metastasizes (spreads to other tissues)

how does migration on ECM happen?

1) actin leads a projection in the cell (along the ECM) 2) N-WASP attaches to actin and causes actin to sink into ECM 3) cofilin binds to N-WASP and actin complex; invadopodium forms

induction of gene transcription by MAP kinase

1) active, dimeric MAP kinase activates p90^RSK (using 2 ATP hydrolyses total- one on each MAP kinase) 2) MAP kinase also enters nucleus (crosses nuclear mem) 3) active p90^RSK inside nucleus phosphorylates SRF (using an ATP hydrolysis) 4) active, dimeric MAP kinase in nucleus doubly phosphorylates TCF (using 1 ATP hydrolysis on 1 side) 5) 2 (p90^RSK-)phosphorylated SRFs and a (MAP-)doubly-phosphorylated TCF transcribe c-fos and c-jun genes

ex of proto-oncogene products

1) anti-apoptotic pro 2) components of signaling and signal transduction pathways that result in proliferation 3) transcription factors

ex of tumor suppressor products

1) apoptosis promoting proteins 2) inhibitors of cell-cycle progression 3) checkpoint-control proteins that assess dna/chromosomal damage 4) components of signal pathways that restrain cell proliferation

steps in process of metastasis

1) cells grow as a benign tumor in epithelium (kept away from connective tissue by the basal lamina) 2) break through basal lamina 3) invade capillary 4) travel through bloodstream (less than 1/1000 cells will survive to form metastasis) 5) adhere to blood vessel wall in liver 6) escape from blood vessel (extravasation) 7) proliferate to form metastasis in liver

___ in Burkitt's lymphoma leads to ___ of the Myc transcription factor in ____ and their growth into a lymphoma

1) chromosomal translocation 2) overproduction 3) lymphocytes

when myc gene expression is inactivated by _____, proliferation of ____ stopped, and there was ____

1) doxycyclin 2) osteogenic sarcomas 3) differentiation into mature osteocytes

types of proto-oncogenes

1) growth factors e.g. PDFG (SIS) 2) growth factor receptors e.g. EGF receptor (HER) 3) protein kinases or proteins that activate protein kinases eg. Src, Ras, Raf 4) proteins that control cell cycle e.g. Cyclin D1 5) proteins that affect apoptosis eg. Bcl-2 6)transcription factors eg. MYC

example of mutations needed for progression of colon cancer

1) loss of APC tumor-suppressor gene (chromosome 5) 2) activation of K-ras oncogene (chromosome 12) 3) loss of p53 tumor suppressor gene (chromosome 17) 4) other changes

the stages of development of cervical cancer

1) low grade intraepithelial neoplasia 2) high grade intraepithelial neoplasia 3) invasive carcinoma

how does an underactivity (loss of function) mutation happen?

1) mutation event inactivates tumor suppressor gene 2) second mutation event inactivates second gene copy 3) two inactivating mutations functionally eliminate the tumor suppressor gene, promoting cell transformation 4) cell en route to cancer

first steps in metastasis of breast carcinoma

1) primary tumor 2) degradation of basement membrane by invadopodia 3) EGF (epidermal growth factor) secreted from macrophages and diffused from blood vessels 4) carcinoma cells migrate along ECM (extracellular matrix) fibers 5) degradation of basement membrane (of blood vessel) by invadopodia

what are the 6 biological properties of cancer?

1) resisting cell death 2) sustaining proliferative signaling 3) evading growth suppressors 4) activating invasion and metastasis 5) enabling replicative immortality 6) inducing angiogenesis

how does an overactvity (gain of function) mutation happen?

1) single mutation event creates oncogene; 2) activating mutation enables oncogene to promote cell transformation 3) cell en route to cancer

_____ to Raf-B gene have excellent results in patients with ____

1) very strong and selective 2) melanoma

MAP

A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine, threonine, and tyrosine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.[1]

significance of BCR gene

A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein that is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint.[5]

proliferative tissue or tumor respiratory pathway

AEROBIC GLYCOLYSIS (WARBURG EFFECT) (with or without O2): same exact pathway as normal cells, but produces way more lactate and only 4mol ATP/ mol glucose

normal anaerobic respiratory pathway

ANAEROBIC GLYCOLYSIS: glucose--> pyruvate-->lactate+ 2mol ATP/ mol glucose

Ras

All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction). Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours. When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation and survival. Mutations in ras genes can lead to the production of permanently activated Ras proteins. As a result, this can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals. Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer.[1] The 3 Ras genes in humans (HRas, KRas, and NRas) are the most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20% to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer).[2] For this reason, Ras inhibitors are being studied as a treatment for cancer and other diseases with Ras overexpression.

BCR gene

Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The protein has serine/threonine kinase activity and is a GTPase-activating protein for RAC1 and CDC42.[4]

cancer in situ

An early stage cancer in which the cancerous growth or tumor is still confined to the site from which it started, and has not spread to surrounding tissue or other organs in the body. When cancer in situ involves cells that line the internal organs, or epithelial cells, it is called carcinoma in situ.

which gene mutation shows up in the greatest percentage of colon cancers in humans?

Apc

example of proteins that affect apoptosis

Bcl-2

what is Bcl-2

Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis.[5][6] Bcl-2 is specifically considered an important anti-apoptotic protein but it is NOT considered a proto-oncogene because it is not a growth signal transducer.

c-jun

Both Jun and its dimerization partners in AP-1 formation are subject to regulation by diverse extracellular stimuli, which include peptide growth factors, pro-inflammatory cytokines, oxidative and other forms of cellular stress, and UV irradiation. For example, UV irradiation is a potent inducer for elevated c-jun expression.[4] The c-jun transcription is autoregulated by its own product, Jun. The binding of Jun (AP-1) to a high-affinity AP-1 binding site in the jun promoter region induces jun transcription. This positive autoregulation by stimulating its own transcription may be a mechanism for prolonging the signals from extracellular stimuli. This mechanism can have biological significance for the activity of c-jun in cancer.[5] Also, the c-jun activity can be regulated by the ERK pathway. Constitutively active ERK is found to increase c-jun transcription and stability through CREB and GSK3. This results in activated c-jun and its downstream targets such as RACK1 and cyclin D1. RACK1 can enhance JNK activity, and activated JNK signaling subsequently exerts regulation on c-jun activity.[6] Phosphorylation of Jun at serines 63 and 73 and threonine 91 and 93 increases transcription of the c-jun target genes.[7] Therefore, regulation of c-jun activity can be achieved through N-terminal phosphorylation by the Jun N-terminal kinases (JNKs). It is shown that Jun's activity (AP-1 activity) in stress-induced apoptosis and cellular proliferation is regulated by its N-terminal phosphorylation.[8] Another study showed that oncogenic transformation by ras and fos also requires Jun N-terminal phosphorylation at Serine 63 and 73.[9] Cell cycle progression[edit] Studies show that c-jun is required for progression through the G1 phase of the cell cycle, and c-jun null cells show increased G1 arrest. C-jun regulates the transcriptional level of cyclin D1, which is a major Rb kinase. Rb is a growth suppressor, and it is inactivated by phosphorylation. Therefore, c-jun is required for maintaining sufficient cyclin D1 kinase activity and allowing cell cycle progression.[4] In cells absent of c-jun, the expression of p53 (cell cycle arrest inducer) and p21 (CDK inhibitor and p53 target gene) is increased, and those cells exhibit cell cycle defect. Overexpression of c-jun in cells results in decreased level of p53 and p21, and exhibits accelerated cell proliferation. C-jun represses p53 transcription by binding to a variant AP-1 site in the p53 promoter. Those results indicate that c-jun downregulates p53 to control cell cycle progression.[10] Anti-apoptotic activity[edit] UV irradiation can activate c-jun expression and the JNK signaling pathway. C-jun protects cells from UV-induced apoptosis, and it cooperates with NF-κB to prevent apoptosis induced by TNFα. The protection from apoptosis by c-jun requires serines 63/73 (involved in phosphorylation of Jun), which is not required in c-jun-mediated G1 progress. This suggests that c-jun regulates cell cycle progression and apoptosis through two separated mechanisms.[4] A study utilized liver-specific inactivation of c-jun in hepatocellular carcinoma, which showed impaired tumor development correlated with increased level of p53 protein and the mRNA level of the p53 target gene noxa. Also, c-jun can protect hepatocytes from apoptosis, as hepatocytes lacking c-jun showed increased sensitivity to TNFα-induced apoptosis. In those hepatocytes lacking c-jun, deletion of p53 can restore resistance toward TNFα. Those results indicate that c-jun antagonizes the proapoptotic activity of p53 in liver tumor.[11]

activation of a proto-oncogene to an oncogene: chromosome rearrangement

EITHER: *nearby regulatory dna sequence causes NORMAL protein to be OVERPRODUCED OR **fusion to actively transcribed gene produces HYPERACTIVE fusion protein

normal function of caretaker genes

repair or prevent dna damage (take care of the dna)

erbb oncoprotein

ErbB-1 and ErbB-2 are found in many human cancers, and their excessive signaling may be critical factors in the development and malignancy of these tumors.[2]

what happens after Sos promotes dissociation of GDP from Ras?

GTP binds and active Ras dissociates from Sos

what does the position 12 RasD mutation entail?

Gly is replaced by another aa

what is GRB2?

Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.[3][4] The protein encoded by this gene binds receptors such as the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. Grb2 is widely expressed and is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. It is thus not surprising that targeted gene disruption of Grb2 in mice is lethal at an early embryonic stage. Grb2 is best known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, ERK1,2. Grb2 is composed of an SH2 domain flanked on each side by an SH3 domain.

what do proto-oncogenic growth factor receptors look like?

HER2 (EGF receptors)

what pathway does a mutation in p53 affect?

response to stress and DNA damage

how does Imatinib (Gleveec) inhibit the activity of ABL kinase (in a BRC-ABL fusion protein)

Imatinib binds to active site and inhibits substrate (ex. JAK2 and STAT5) binding

what can the BCR-ABL (constitutively active kinase) fusion protein activate by phosphorylation?

JAK2, STAT5

what is JAK?

Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases,[1]) but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings and endings, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first. Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The receptors exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline-rich region in each intracellular domain that is adjacent to the cell membrane and called a box1/box2 region. After the receptor associates with its respective cytokine/ligand, it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other. The JAK autophosphorylation induces a conformational change within itself, enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factors called STATs (Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription).[4] The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus, where they regulate transcription of selected genes. Some examples of the molecules that use the JAK/STAT signaling pathway are colony-stimulating factor, prolactin, growth hormone, and many cytokines.

difference between MAP and MEK

MEK is a dual specificity kinase: Tyr and Ser/Thr, while MAP is only Ser/Thr

MEK

Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).

what do proto-oncogenic growth factors look like?

they bind to PM of cell from outside the cell

c-myc

Myc (c-Myc) is a regulator gene that codes for a transcription factor. The protein encoded by this gene is a multifunctional, nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular transformation.[3]capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation, and stem cell self-renewal. Myc is a very strong proto-oncogene and it is very often found to be upregulated in many types of cancers. Myc overexpression stimulates gene amplification,[10] presumably through DNA over-replication. There have been several studies that have clearly indicated Myc's role in cell competition.[11] A major effect of Myc is B cell proliferation.[12] c-Myc induces MTDH(AEG-1) gene expression and in turn itself requires AEG-1 oncogene for its expression.

normal aerobic respiration pathway

OXIDATIVE PHOSPHORYLATION: glucose--> pyruvate (some of which becomes lactate)-->(in mitochondrion, combined with O2)-->release of CO2 and 36mol ATP/mol glucose

an example of proto-oncogenic growth factor

PDGF (Platelet-Derived Growth Factor, causes angiogenesis)

Src

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src or simply c-Src , is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. This protein phosphorylates specific tyrosine residues in other proteins. An elevated level of activity of c-Src tyrosine kinase is suggested to be linked to cancer progression by promoting other signals.[3] c-Src includes an SH2 domain, an SH3 domain, and a tyrosine kinase domain.

Raf

RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1 is an enzyme[5] that in humans is encoded by the RAF1 gene.[6][7] The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase kinase kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases.[8] C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases.

what does active Ras do?

RasGTP (active Ras) dissociates from Sos and signals

what is the active form of Ras?

RasGTP; activated by Sos

SRF

Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors.[4] This protein binds to the serum response element (SRE) in the promoter region of target genes. This protein regulates the activity of many immediate early genes, for example c-fos, and thereby participates in cell cycle regulation, apoptosis, cell growth, and cell differentiation. This gene is the downstream target of many pathways; for example, the mitogen-activated protein kinase pathway (MAPK) that acts through the ternary complex factors (TCFs).[5][6] SRF is important during the development of the embryo, as it has been linked to the formation of mesoderm.[7][8] In the fully developed mammal, SRF is crucial for the growth of skeletal muscle.[9] Interaction of SRF with other proteins, such as steroid hormone receptors, may contribute to regulation of muscle growth by steroids.[10] Interaction of SRF with other proteins such as myocardin or Elk-1 may enhance or suppress expression of genes important for growth of vascular smooth muscle.

what do the 2 SH3 domains of GRB2 bind to?

Sos

once GRB2 binds to activated receptor tyrosine kinase, what happens?

Sos binds to SH3 domains of GRB2 (the head of the fish, SH2, binds cytosolic "tail" of RTK, and the tail is bitten by Sos)

What does Sos do after it binds to GRB2 and RasGDP binds to Sos?

Sos promotes dissociation of GDP from Ras; GTP binds and active Ras dissociates from Sos

origin of mutations in caretaker genes

arise by: 1) deletion 2) point mutation 3) methylation (JUST LIKE THE OTHER LOSS OF FUNCTION CANCER CAUSING GENES IE TUMOR SUPPRESSOR GENES)

what pathway does a mutation in Smad4 affect?

TGFB signaling

what pathway does a mutation in TGFB receptor II affect?

TGFB signaling

TCF

The TCF/LEF family is a group of transcription factors which bind to DNA through a high mobility group domain. They are involved in the Wnt signaling pathway, where they recruit the coactivator beta-catenin to enhancer elements of genes they target. They can also recruit members of the Groucho family of corepressors.[1]

MAP/ERK pathway

The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, including MAPK (mitogen-activated protein kinases, originally called ERK, extracellular signal-regulated kinases), which communicate by adding phosphate groups to a neighboring protein, which acts as an "on" or "off" switch. When one of the proteins in the pathway is mutated, it can become stuck in the "on" or "off" position, which is a necessary step in the development of many cancers. Components of the MAPK/ERK pathway were discovered when they were found in cancer cells. Drugs that reverse the "on" or "off" switch are being investigated as cancer treatments.[1]

origin of mutations in proto-oncogenes

arise by: 1) point mutation 2) chromosomal translocation 3) amplification

the hallmarks of cancer

at least 6 biological properties acquired during the multistep development of human tumors

what pathway does a mutation in Apc affect?

Wnt signaling

what pathway does a mutation in B-catenin affect?

Wnt signaling

osteocyte

a bone cell, formed when an osteoblast becomes embedded in the matrix it has secreted.

osteogenic sarcoma

a cancerous tumor in a bone.

fibroblast

a cell in connective tissue that produces collagen and other fibers.

what is Neu oncoprotein?

a ligand-independent receptor oncoprotein

gp55

a viral oncoprotein produced by the spleen focus-forming virus, which induces erythroleukemia

aneuploidy

abnormal number of chrom in pairings (aberrant chromosome complements)

cancer is caused mainly by

accumulation of mutations in the somatic cells of the afflicted individual; some ppl have inherited mutations that predispose them to develop cancer

what kinase translocates to the nucleus in dimerized form and activates many transcription factors?

activated MAP kinase

what happens when Epo binds an erythropoietin receptor?

activation of JAK kinases using ATP hydorlysis

how do cancer cells produce energy?

aerobic glycolysis

the incidence of human cancers increases as a function of

age

v-Src

an oncoprotein encoded by Roux sarcoma virus: Myr N-term, SH3 dom, SH2 dom, kinase (no Tyr on C-term--> CONSTITUTIVELY ACTIVE KINASE)

Ras mutants that cannot hydrolyze GTP ___

are permanently in the GTP bound state and contribute to oncogenic transformation

origin of mutations in tumor suppressor genes

arise by: 1) deletion 2) point mutation 3) methylation

the Gly-12 mutation ____

blocks the functional binding of GAP

c-fos

c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos.[3]c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun (part of Jun family of transcription factors), resulting in the formation of AP-1 (Activator Protein-1) complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression.[5] It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers. c-fos is a 380 amino acid protein with a basic leucine zipper region for dimerisation and DNA-binding and a transactivation domain at C-terminus. Unlike Jun proteins, it cannot form homodimers, only heterodimers with c-jun. In vitro studies have shown that Jun-Fos heterodimers are more stable and have stronger DNA-binding activity than Jun-Jun homodimers.[6] A variety of stimuli, including serum, growth factors, tumor promoters, cytokines, and UV radiation induce their expression. The c-fos mRNA and protein is generally among the first to be expressed and hence referred to as an immediate early gene. It is rapidly and transiently induced, within 15 minutes of stimulation.[7] Its activity is also regulated by posttranslational modification caused by phosphorylation by different kinases, like MAPK, cdc2, PKA or PKC which influence protein stability, DNA-binding activity and the trans-activating potential of the transcription factors.[8][9][10] It can cause gene repression as well as gene activation, although different domains are believed to be involved in both processes. It is involved in important cellular events, including cell proliferation, differentiation and survival; genes associated with hypoxia; and angiogenesis;[11] which makes its dysregulation an important factor for cancer development. It can also induce a loss of cell polarity and epithelial-mesenchymal transition, leading to invasive and metastatic growth in mammary epithelial cells.[12] The importance of c-fos in biological context has been determined by eliminating endogenous function by using anti-sense mRNA, anti-c-fos antibodies, a ribozyme that cleaves c-fos mRNA or a dominant negative mutant of c-fos. The transgenic mice thus generated are viable, demonstrating that there are c-fos dependent and independent pathways of cell proliferation, but display a range of tissue-specific developmental defects, including osteoporosis, delayed gametogenesis, lymphopenia and behavioral abnormalities. c-fos PLAYS A ROLE IN INDICATING NEURONAL ACTIVITY AND IMORTANT FOR STUDY OF ADDICTIONS!! https://en.wikipedia.org/wiki/C-Fos

the activity of ___ spikes more after the addition of serum to quiescent 3T3 cells

c-fos

the activity of which proto-oncogene spikes sooner after the addition of serum to quiescent 3T3 cells?

c-fos

mutations often _____ to induce cancer

cooperate (ex: myc+ras^V12 causes cancer faster than either myc or even ras^V12 alone)

the binding of GRB2 and Sos ___

couples the (active, dimerized) EGF receptor to inactivate Ras

aberrant

departing from an accepted standard.

what happens when a ligand binds the receptor tyrosine kinase (RTK)?

dimerization and phosphorylation of activation lip tyrosines (from ATP hydrolysis)

what happens when a ligand binds to the ligand-binding site of a cytokine receptor?

dimerization and phosphorylation of activation lip tyrosines (from ATP)--> JAK active

ex of caretaker gene product

dna repair enzymes

normal cells - serum growth factors

don't grow too much

MEK is a ___

dual-specificity kinase: Tyr and Ser/Thr

what does active p90^RSK do?

enters nucleus (crosses nuclear mem) and phosphorylates SRF

what is an EGF receptor?

epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.

adenocarcinoma

epithelial MALIGNANT tumor: invasive, cancerous gland tubules invade normal gland tubules

capillaries are lined with

epithelial cells

extravasation

escape from blood vessel and into surrounding tissue after being transported from some other place in the body

what do "inactive" receptor tyrosine kinases (RTKs) look like?

exterior: ligand-binding sites, transmembrane alpha helix cytosol: poorly active protein tyrosine kinase w activation lip

effects of mutation in proto-oncogenes

gain of function mutations allow unregulated cell proliferation and survival

what happens when gp55 binds an erythropoietin receptor?

gp55 actually adds a pair of transmembrane domains. activation of JAK kinase using ATP hydrolysis

cancer cells + serum growth factors

grow at a faster linear rate

cancer cells - serum growth factors

grow at a linear rate

growth properties of cancer cells

grow in clumps (foci)

growth properties of normal cells

grow in monolayer

normal cells + serum growth factors

grow steadily, but not endlessly (eventually stop growing)

what does a normal EGF receptor (a proto-oncogene receptor protein) look like?

has a ligand-binding site on cell's exterior side

what does active p90^RSK look like?

has a phosphate; activated by active, dimeric MAP kinase + 2 ATP hydrolyses

normal cell division +normal apoptosis results in

homeostasis

what is HER?

human epidermal growth factor receptor

3T3 cells

immortal mouse fibroblast cells, with mutations in p19Arf and p53

quiescent

in a state or period of inactivity or dormancy.

cancer cells can multiply

in the absence of growth factors required for proliferation of normal cells

what binds to Sos after Sos binds to GRB2?

inactive RasGDP (which has a tail in the PM)

what does Epo do?

induces cell proliferation and differentiation of erythroid progenitor cells leading to production of erythrocytes

normal function of tumor-suppressor genes

inhibit cell survival or proliferation

3 types of cytokines

interleukins, interferons, erythropoietin (Epo)

what is Epo secreted by?

kidney cells

what does inactive p90^RSK look like?

lacks a phosphate

what activates a cytokine receptor?

ligand binding to extracellular ligand-binding site.

effects of mutation in caretaker genes

loss of function mutations allow mutations to accumulate

effects of mutation in tumor suppressor genes

loss of function mutations allow unregulated cell proliferation and survival

where do polyps develop?

lumen of colon

what does a deletion mutation in EGF receptor (a proto-oncogene receptor protein) cause?

makes EGF a ErbB oncoprotein, which lacks ligand-binding site, is constitutively dimerized, and has a constitutively active protein tyrosine kinase

what does a Val->Gln oncogenic mutation in Her2 receptor (proto-oncogene receptor) cause?

makes Her2 a Neu oncoprotein, which has glutamine alpha helix transmembrane domain and a constitutively active protein tyrosine kinase

when tumor cells invade blood vessels,

metastasis can occur

proteins that affect apoptosis are targetted to ___

mitochondrion

where do most oncogenic active Ras mutants (RasD) have a mutation?

most RasD have a mutation at position 12: Gly replaced by another aa

tumorigenesis

multistep process characterized by the progression of genetic alterations in a single line of cells no longer responsive to normal growth control and better able to invade normal tissues leading to metastasis

which gene mutation is often silenced by methylation?

mutation in MLH1 and other DNA mismatch repair genes

genetic properties of proto-oncogenes

mutations are genetically dominant (THEY'RE PROTO CAUSE THEY'RE PROMOTED--DOMINANT)

genetic properties of caretaker genes

mutations are genetically recessive

genetic properties of tumor suppressor genes

mutations are genetically recessive

___ is continuously needed for tumor growth

myc

what activates a erythropoietin (Epo) receptor?

natural ligand, Epo, or a viral oncoprotein

what is the inactive form of MEK?

no phosphate

what is the inactive form of MAP kinase?

no phosphates

c-Src

normal Src tyrosine kinase: Myr N-term, SH3 dom, Sh2 dom, Kinase, and Tyr on C-term that gets phosphorylated via AtP hydrolysis by Csk

composition of wall of colon

normal colon epithelial cells, basement membrane, tissue containing blood vessels

what do cytokine receptors without bound ligand look like?

on exterior: have ligand binding sites, transmembrane alpha helix in cytosol: JAK kinase with activation lip

Ras is an

oncogene

what class is the gene B-catenin?

oncogene

what class is the gene K-Ras?

oncogene

if 2 genes are in a single pathway,

only 1 of the components is mutated in an individual cancer

cancers of epithelia (unfortunately, more popular)

oral, pharynx, digestive, respiratory, breast, reproductive tract, urinary sys

what does the SH2 domain of GRB2 bind to?

phosphate of phosphorylated tyrosine residues on activated (dimerized) EGF receptor

what happens after a receptor tyrosine kinase (RTK) is activated?

phosphorylation of additional tyrosine residues (using ATP hydrolysis)

what happens once JAK is active?

phosphorylation of additional tyrosine residues (w ATP to ADP rxn)

as a result of chromosomal translocation, the myc gene is

placed near the antibody heavy chain leading to overproduction of myc

normal function of proto-oncogenes

promote cell survival or proliferation (promo of onco)

what binds to EGF receptor cytosolic side?

protein kinases or proteins that activate protein kinases: Src, Ras, Raf

Raf is a ____ kinase

serine/threonine

MAP kinase (ERK) is a ___

serine/threonine kinase

during low grade intraepithelial neoplasia, there are

still a lot of normal cells

fibroblasts and white blood cells are

stromal cells

_____ are required for development of colon cancer

successive mutations

what do many tumors, including colon, mammary, skin, bladder, lung carcinomas, neuroblastomas, and leukemias have in common?

they all produce RasD

during high grade intraepithelial neoplasia, there are

tons of cancerous/abnormal/transformed cells, but still contained within the epithelium

during invasive carcinoma,

transformed cells invade connective tissue

conversion of Alb proto-oncogene into an oncogene in patients with chronic myelogenous leukemia

translocation of ABL gene from chrom9 to (the philadelphia)chrom22, next to the BCR gene. this causes a BCR-ABL fusion protein to be trancribed/translated.

increased cell division + normal apoptosis results in

tumor

normal cell division + decreased apoptosis results in

tumor

____ plays a role in tumorigenesis

tumor microenvironment

what class is the gene Apc?

tumor suppressor

what class is the gene Smad4?

tumor suppressor

what class is the gene TGFB receptor II?

tumor suppressor

what class is the gene p53?

tumor suppressor

what class is the gene MLH1 and other DNA mismatch repair genes?

tumor suppressor (genetic stability)

cancer cells have

uncontrolled cell proliferation

what does a normal Her2 receptor (a proto-oncogene receptor protein) have in its alpha helix transmembrane domain?

valine

what is the active form of MAP kinase?

with 2 phosphates; activated by MEK

what is the active form of MEK?

with a phosphate; activated by Raf