The molecular biology of cancer
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42 terms
Terms | Definitions |
|---|---|
 Cancer cells | -do not require growth stimulatory signals -resistant to growth-inhibitory signals -resistant to apoptosis -they have infinite proliferative capacity -they can grow independent of structural support, such as ECM (loss of anchorage dependence) |
| Leukemia symptoms | -variety of hemorrhagic (bleeding) manifestations caused by a decreased number of platelets -b/c of uncontrolled proliferation of white cells within the limited space of the marrow, the normal platelet precursor (the megakaryocytes) in the marrow are "squeezed" or crowded and fail to develop into mature platelets |
| 3 criteria to distinguish cancer cells from normal cells | 1) requirement for serum in the cell culture medium to stimulate growth -transformed cells have, in general, a reduced requirement for serum (10% that required for normal cells to grow) 2) Ability to grow without attachment to supporting matrix (anchorage dependence) 3) ability of cells to form tumors when thet are injected into mice that lack an immune system |
| Transformation process | 1) begins with damage to DNA caused by chemical carcinogens, UV light, viruses, or replication errors -mutations can result from the damaged DNA if it is not repaired properly or if it is not repaired before replication occurs -mutations can also be inherited 2) When a cell w/ one mutation proliferates, this clonal expansion results in a substantial population of cells containing this one mutation, from which one cell may may acquire a second mutation relevant to control of cell growth or death **with each clonal expansion the probability of another transforming mutation increases 3) as mutations ACCUMULATE in genes that control proliferation, subsequent mutations occur even more rapidly, until the cell acquire the multiple mutations (4-7) necessary for full transformation |
| proto-oncogenes | -genes that regulate cellular proliferation and differentiation -encode proteins that are growth factors, growth-factor receptors (can be permanently switched on even without the presence of a ligand), signal transduction proteins, transcription factors, cell-cycle regulators, and regulators of apoptosis *all of the proteins in growth-factor signal transduction cascades are proto-oncogenes **GOF mutations here --> either a MORE ACTIVE protein is produced or an increased amount of the normal protein is synthesized |
| The transforming mutations occur in genes that ____ (4) | -regulate cellular proliferation and differentiation (proto-oncogenes) -suppress growth (tumor suppressor genes) -target irreparably damaged cells for apoptosis -repair damaged DNA **GAIN OF FUNCTION mutations in proto oncogenes --> oncogenes **LOSS OF FUNCTION mutations for tumor suppressor genes and repair enzyme genes |
| Malignant neoplasms of EPITHELIAL CELL ORIGIN (including the intestinal lining, cells of the skin, and cells lining the airways of the lungs) are called _____ | -Carcinomas **IF the cancer grows in a glandlike pattern = ADENOCARCINOMA |
| Moles | -nevi -tumors of the skin -formed by melanocytes that have been transformed from highly dendritic single cells interspersed among other skin cells to round oval cells that grow in aggregates or "nests" -additional mutations may turn the mole into a malignant melanoma |
| The ____ and ____ atoms in DNA bases are the targets for a variety of of electrophiles (electron seeking chemical groups) | -oxygen -nitrogen |
| Chemical carcinogens | -are generally stable lipophilic compounds, that like dimethylnitrosamine, must be activated by metabolism in the body to react with DNA *many chemotherapeutic agents, which are designed to kill proliferating cells act as carcinogens and may cause new mutations and tumors while eradicating the old $$ each chemical carcinogen makes a characteristic modification in a DNA base |
| Radiation and UV light | -causes the formation of PYRIMIDINE DIMERS - this damage requires nucleotide excision repair (pathway that requires products of at least 20 genes) -with excessive exposure to the sun, this pathway is overwhelmed and some damage remains unrepaired **UVB (280-320) carries highest risk of skin cancer |
| GOF mutations in Proto-oncogenes | 1) radiation and chemical carcinogens acts by causing a mutation in the REGULATORY REGION of a gene --> increased rate of production of the the protein or by producing a mutation in the coding portion of the oncogene that results in the synthesis of a protein of slightly different amino acid composition capable of transforming the cell 2) The entire proto-oncogene or a portion of it may be transported or translocated from one position in the genome to another. In its new location, the proto-oncogene may be expressed under the control of a promoter that is regulated differently than the normal promoter --> allows it to be expressed in tissues where it is normally not expressed or at a higher level than normally expressed -if only a portion of the proto-onncogene is translocated, it may be expressed as a truncated protein with altered properties, may fuse with other proteins --> hyperactive protein --> inappropriate cell growth 3) POG may be amplified -> multiple copies of the gene are produced in a single cell -i.e oncogene N-myc is amplified in some neuroblastomas; erb-B2 in some breast carcinomas 4) an oncogenic virus infects a cell, its oncogene may integrate into the host cell genome, permitting production of the abnormal oncogene protein --> cell may be transformed and exhibit an abnormal growth pattern -virus may also just insert a STRONG PROMOTER in the host cell genome |
| Burkitt lymphoma | -general name for a number of types of B-cell malignancies, results from a translocation b/w chromosomes 8 and 14 -the translocation of genetic material moves the proto-oncogene transcription factor c-myc (normally on 8) to 14. The translocated gene is now under the control of the promoter region for the immunoglobulin heavy-chain --> inappropriate overexpression of c-myc |
| Mutations in repair enzymes | -repair enzymes are first line of defense preventing conversion of chemical damage in DNA to a mutation **DNA repair enzymes are tumor suppressor genes example: inherited mutations in the tumor-suppressor genes brca1 and brca2 predispose women to the development of breast cancer -the protein products of these genes play roles in DNA repair, recombination, and regulation of transcription also: HNPCC (hereditary nonpolyposis colorectal cancer) - mutations in enzymes involved in the DNA mismatch repair system |
| Ras (monomeric G protein) is converted to an oncogenic form by ____ | -point mutations that decrease the activity of the GTPase domain of Ras, thereby increasing the length of time it remains in its active form |
| The Philadelphia Chromosome | -typical of Chronic Myelogenous Leukemia (CML) -results from a reciprocal translocation b/w the long arms of chromosome 9 and 22 - as a consequence, a fusion protein is produced that contains the N-terminal region of the Bcr protein from 22 and the C-terminal region of the Abl protein from 9. *Abl is a proto-oncogene, and the resulting fusion protein (Bcr-Abl) has lost its regulatory region and is constitutively active -when it is active, Abl stimulates the Ras pathway of signal transduction --> cell proliferation; Ras in its active form activates serine-threonine kinase Raf (a MAP kinase kinase kinase) --> which activates MEK (a MAP kinase) --> which activates MAP kinase --> phosphorylation of cytoplasmic and nuclear proteins followed by increased transcription of the transcription factor proto-oncogenes myc and fos -MAP kinase also directly activates AP-1 Transcription factor (a heterodimer of fos and jun protein products) --> targets genes involved in proliferation (same mech as myc) |
| brca1 vs. brca2 | -brca1 also linked to ovarian cancer -brca2 linked to pancreatic cancer -men with inherited brca2 mutations dev. breast cancer; but men who carry brca1 mutations do not |
| The gene for the _______ is overexpressed in 10-20% of breast cancer cases | -human epidermal growth-factor receptor (HER2, c-erbB-2) -when this gene is overexpressed prognosis for recovery is poor - pts. display shorter disease-free intervals, increased risk for metastasis, and a resistance to therapy **Herceptin - is a monoclonal antibody with specificity to the HER2 protein. Some success but not all tumors are responsive to it. complete genotyping of breast cancer cells may be necessary |
| Synthesis of C-myc transcription factor | -expressed only during the S phase of the cell cycle and is tightly regulated to do so |
| CDKs, cyclins, CKIs, CAKs | -transitions (G1/S, S/G2, G2/M) -Cyclin dependent kinases require a specific cyclin to be active -CKIs - slow cell-cycle progression by binding and inhibiting the CDK-cyclin complexes -CDKs are also regulated through activating phosphorylation by CAK (cyclin-activating kinases) and inhibitory hyperphosphorylation kinases $$ Cells are committed to DNA replication and division once it enters the S phase |
| Regulatory proteins at G1/S checkpoint | -cdk4 -cdk6 *both are constantly produced throughout cell cycle -cyclin D -synthesis is induced only after GF-stimulation of a quiescent cell -the retinoblastoma gene product (Rb) -a class of transcription factors known collectively as E2F ** In quiescent cells, Rb is complexed with E2F --> inhibition of these transcription factors that normally promote growth |
| Upon growth-factor stimulation ____ | -the cyclin Ds are induced (3 types of cyclin D: D1, D2, D3) -they bind to cdk4 and cdk6, converting them to active protein kinases *One of the targets of cyclin/cdk phosphorylation is the Rb protein - phosphorylation of Rb releases it from E2F, and E2F is then free to activate the transcription genes required for entry into S. *the Rb protein is a TUMOR-SUPPRESSOR GENE |
| The proteins induce by E2F include ___ | -cyclin E - synthesis of this allows it to complex with cdk2, forming another active cyclin complex that retains activity into S phase. cyclin E1-cdk2 complex HYPERPHOSPHORYLATES Rb keeping it an in inactive state -cyclin A - also complexes with Cdk2 and it phosphorylates and inactivates the E2F family of transcription factors --> $$ ensures that the signals are not present for extended periods of time -cdc25A (an activating protein phosphatase) -proteins required to bind at origins of replication to initiate DNA synthesis -cyclins are removed by regulated proteolysis |
| The CKIs regulating cyclin/cdk expression in the G1 phase of the cell cycle fall into 2 categories: | 1) Cip/Kip family (p21, p27, p57) - have BROAD specificity and inhibit ALL cyclin-CDK complexes 2) INK4 family (p15, p16, p18, p19) - specific for the cyclin D-cdk4/6 family of complexes (inhibitors of cyclin-dependent kinase-4) **regulation of CKIs is complex but some is induced by DNA damage to the cell and halts cell cycle progression until damage can be repaired (i.e p21 - if damage cannot be repaired, an apoptotic pathway is selected and the cell dies) |
| Melanoma-associted genes | -p16 (an inhibitor of cdk 4) -CDK4 |
| Tumor suppressor genese vs. proto-oncogenes | -tumor-suppressor genes contribute to the development of cancer when BOTH copies of the gene are inactivated -this is different from proto-oncogenes which only need ONE allele to be mutated to initiate transformation |
| The retinoblastoma gene (Rb) | -tumor suppressor gene/cell-cycle regulator -functions in transition from G1 to S phase *regulates the activation of the E2F family of transcription factors *If an individual inherits a mutated copy of the rb allele, there is a 100% chance of the individual developing retinoblastoma, b/c of the high probability that the second allele of rb will gain a mutation (familial retinoblastoma) |
| p53 | -the p53 protein is a transcription factor that regulates the cell cycle and apoptosis, programmed cell death *loss of the p53 allele is found in more than 50% of human tumors -p53 acts as the guardian of the genome by halting replication in cells that have suffered DNA damage and targeting unrepaired cells to apoptosis -levels of p53 rise in response to DNA-damaging mutagens -acting as a transcription factor, stimulates transcription of p21 (a member of the Cip/Kip family of CKIs) that inhibits the cyclin/CDK complexes; ultimately preventing E2F from taking the cell into the S phase **p53 also stimulates the transcription of a number of DNA repair enzymes (GADD45) $ If DNA is successfully repaired, p53 induces its own downregulation, through the activation of the mdm2 gene $ if DNA repair is not successful, p53 activates a number of genes involved in apoptosis, including bax and IGF-BP3 (the protein product binds the receptor for insulinlike growth factor --> induces apoptosis |
| Inheritance of a mutation in p53 --> ____ | -Li-Fraumeni syndrome - multiple types of tumors |
| Regulators of Ras (Tummor suppressor genes) | -Ras family of proteins is involved in signal transduction for many hormones and growth factors (therefore is oncogenic) -GAPs (GTPase-activating proteins) interrupt these pathways - vary among cells *Neurofibrin (product of tumor suppressor gene NF-1) is a NERVOUS SYSTEM SPECIFIC GAP that regulates the activity of Ras in neuronal tissue *the growth signal is transmitted so long as Ras binds GTP *Binding of NF-1 to Ras activates the GTPase domain of Ras, which hydrolyzes GTP--> GDP, thereby stopping the growth signal |
| The Patched receptor protein gene ____ Smoothened (its co-receptor protein) Binding of a hedgehog ligand to Patched -->_____ | -inhibits -releases the inhibition of smoothened, which then transmits an ACTIVATING signal to the nucleus, stimulating new gene transcription ** Smoothened is a proto-oncogene - gain of function here (onco-gene) it can signal in absence of a hedgehog signal, even in the presence of Patched ** Patched is a tumor-suppressor gene - if Patched suffers a loss of function mutation, Smoothened can signal the cell to proliferate even in the absence of hedgehog ligand %% Inherited mutation in either will lead an increased incidence of - BASAL CELL CARCINOMA |
| An inherited mutation in NF-1 can lead to _____ | -NEUROFIBROMATOSIS - a disease primarily of numerous, benign, but painful, tumors of the nervous system |
| Loss of E-cadherin expression may contribute to ______ | -the ability of cancer cells to detach and migrate in metastasis **Individuals who inherit a mutation in E cadherin (CDH1 mutation) are sharply predisposed to developing diffuse-type GASTRIC CANCER |
| The CATENIN proteins 2 functions | 1) anchoring cadherins to actin cytoskeleton 2) Act as transcription factors --> cell proliferation -normally regulated by APC (adenomatous polyposis coli), which activates it for degradation - APC acts as a TUMOR-SUPPRESSOR GENE **Mutations in APC or proteins that interact with it are found in the vas majority of sporadic HUMAN COLON CANCER |
| Apoptosis --> formation of apoptotic bodies with _____ exposed on the external surface | -PHOSPHATIDYLSERINE - a phagocytic marker recognized by macrophages and other nearby phagocytic cells |
| Caspases | -cysteine proteases that cleave peptide bonds next to an ASPARTATE RESIDUE -present in the cell as PROCASPASES, zymogen-type enzyme precursors that are activated by proteolytic cleavage of the inhibitory portion of their polypeptide chain 1) Initiator caspases - specifically cleave other procaspases; activated through two major signaling pathways * Death Receptor pathway - subset of TNF-1 receptors (includes Fas/CD95, TNF-R1, Death Receptor 3 (DR3)). These receptors form a trimer that binds TNF-1 or another death ligand on its external domain and adaptor proteins to its intracellular domain. The TNF-receptor complex forms the scaffold for binding 2 molecules of procaspase 8 (or 10), which AUTOCATALYTICALLY cleave each other to form active caspase 8 (or 10) -caspase 8 and 10 are initiator caspases that ACTIVATE EXECUTION CASPASES 3, 6, and 7 -caspase 3 also cleaves a Bcl-2 protein, Bid, to a form that activates the mitochondrial integrity pathway *Mitochondrial integrity pathway (intracellular signals) -Growth factor withdrawal, cell injury, the release of certain steroids, and an inability to maintain low levels of intracellular calcium: ALL lead to release of CYTOCHROME C from the MITOCHONDRIA -CYTOCHROME C - a necessary protein component of the mitochondrial ETC that is loosely bound to the outside of the inner mitochondrial membrane. Its release initiates APOPTOSIS $$ In the cytosol, cytochrome c binds Apaf and the Apaf/cytochrome c complex binds caspase 9, an initiator caspase -together-> forms APOPTOSOME. The apoptosome, in turn, activates executioner caspases 3,6 and 7 by zymogen cleavage -they activate the executioner caspases 2) Execution caspases - cleave other cellular proteins involved in maintaining cellular integrity (cell adhesion, lamins that form the inner lining of the nuclear envelope, actin, etc) |
| The Bcl-2 family | -DECISION MAKERS that integrate pro-death and anti-death signals to determine whether the cell should commit suicide -the family has both pro and anti apoptotic members 1) antiapoptotic- Bcl-2, Bcl-x, Bcl-w - have at least two ways of antagonizing death signals * insert into the outer mitochondrial membrane to antagonize channel-forming pro-apoptotic factors, thereby decreasing cytochrome c release *may also bind cytoplasmic Apaf so that it cannot form the apoptosome complex 2) Pro-apoptotic family members (2 categories) * ion channel forming members - (Bax) - dimerize with the BH3 only members in the outer mitochondrial membrane and form an ION CHANNEL that promotes CYTOCHROME C RELEASE rather than inhibiting it *BH3 only members (Bim and Bid) $$ normally Bcl-2 acts as a death antagonist by binding Apaf and keeping it in an inactive state |
| Cancer cells bypass Apoptosis | 1) activation of growth factor dependent signaling pathways that inhibit apoptosis such as PDGF/Akt/BAD pathway --> phosphorylation of BAD by Akt -nonphosphorylating BAD acts like Bid in promoting apoptosis. If it is phosphorylated then apoptosis is inhibited 2) MAP kinase --> activates RSK (protein kinase) that phosphorylates BAD and inhibits its activity |
| When Bcl-2 is mutated it is usually _____ and ___ | -oncogenic -usually overexpressed -tips balance to anti-apoptotic stand * Bcl-2 is also a multi-drug-resistant protein and if it is overexpressed it will block the induction of apoptosis by antitumor agents by rapidly removing them from the cell |
| TNM system | T - tumor stage N - number of lymph nodes affected M - presence of metastasis (0 or 1) |
| Mutations associated with malignant melanomas include ___ | -ras (gain of function in growth signal transduction oncogene) -p53 (loss of function) -p16 (loss of function in Cdk inhibitor tumor-suppressor gene) -Cdk4 (gain of function in cell cycle progression oncogene) -cadherin/B-catenin regulation - loss of regulation that requires attachment |
| 3 RNA retroviruses associated with cancer | -HTLV-1 - causes adult T-cell leukemia; viral genome encodes Tax that activates c-sis and c-fos (proto-oncogenes) -HIV - loss of immune mediated tumor surveillance -hepatitis C *there are also DNA viruses -SV40 -papilomavirus (cervical) -adenovirus *all 3 encode proteins that inactivate pRb and p53 |
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