Tumor Suppressor Gene Concepts Flashcards

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Cellular senescence

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A stable, non-dividing state entered by cells in response to stress or oncogenic signals. Senescent cells remain metabolically active and show markers like senescence-associated beta-galactosidase, and they can accumulate in tissues with age or pre-neoplastic lesions. Senescence acts as a barrier to tumorigenesis by halting proliferation of potentially dangerous cells.

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Crisis

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A catastrophic proliferative collapse that occurs after cells bypass senescence but exhaust telomere protection, leading to widespread apoptosis. Crisis is distinct from senescence and commonly follows expression of viral oncoproteins that transiently block senescence. Escape from crisis typically requires telomere maintenance reactivation to allow immortalization.

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Telomeres

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Protective nucleoprotein structures at chromosome ends composed of tandem repeats of the sequence $5'$-$TTAGGG$-$3'$ and associated proteins. They prevent end-to-end chromosome fusion and mask chromosome ends from DNA damage responses. Progressive telomere shortening during cell divisions limits proliferative capacity and acts as a tumor-suppressive mechanism.

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T-loop

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A lariat-like, three-stranded structure formed when the single-stranded 3' telomeric overhang invades the double-stranded telomeric repeat tract. The t-loop helps hide the chromosome end from DNA repair machinery and protects telomeres from being recognized as double-strand breaks. Formation of t-loops is aided by telomere-binding proteins.

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Telomere-binding proteins

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Proteins that specifically bind double-stranded telomeric repeats and the single-stranded 3' overhang to form the telomere nucleoprotein complex. These proteins stabilize t-loops, protect telomeres from exonucleases, and regulate access of telomerase to the ends. Loss or dysfunction of these proteins compromises telomere integrity and genome stability.

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End-replication problem

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A consequence of lagging-strand DNA synthesis where the terminal RNA primer cannot be fully replaced with DNA, causing progressive shortening of linear chromosome ends. This under-replication leads to gradual loss of telomeric repeats with each cell division. The problem underlies the need for specialized telomere maintenance mechanisms.

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Telomere shortening rate

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In many normal human cells, telomeres shorten by about 50–100 base pairs per cell generation due to under-replication and exonucleolytic trimming. This progressive erosion limits proliferative lifespan and prevents unlimited expansion of cell populations. When telomeres shorten below a critical length, protective function is lost and crisis or senescence ensues.

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Telomerase

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A ribonucleoprotein enzyme that elongates telomeric DNA by adding repeats to the 3' overhang, counteracting telomere shortening. Telomerase activity is low in most somatic human cells but high in germ cells, early embryos, and 85–90% of human tumors, contributing to cellular immortalization. Reactivation of telomerase is a common route by which pre-neoplastic cells escape crisis.

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Telomerase core subunits

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The telomerase holoenzyme core consists of a catalytic reverse transcriptase subunit and an RNA template subunit. In humans, the catalytic protein is $hTERT$ and the RNA component is $hTR$, which provides the six-nucleotide template that guides repeat addition to telomeres. The complementary telomeric strand is synthesized later by conventional DNA polymerases.

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hTERT expression

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Expression of the catalytic telomerase subunit $hTERT$ is the limiting factor for telomerase activity in many human somatic cells. Ectopic $hTERT$ expression can prevent crisis and confer unlimited proliferation or immortalization. Conversely, dominant-negative $hTERT$ or loss of activity can induce crisis in tumor cells depending on telomere length.

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ALT mechanism

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Alternative lengthening of telomeres (ALT) is a telomerase-independent pathway some immortalized cells use to maintain telomeres. ALT commonly involves homologous recombination-mediated telomere elongation. Cells using ALT can maintain telomeres without detectable telomerase activity.

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hTERT promoter regulation

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Transcriptional control of $hTERT$ involves multiple activators (e.g., c-Myc, HPV E6, ER81) and repressors (e.g., Menin, p53, Mxd, WT1). Promoter mutations and germline polymorphisms can increase or decrease $hTERT$ transcription, affecting cancer risk and telomerase reactivation in tumors. Frequent promoter mutations in melanoma enhance $hTERT$ expression.

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Telomere Nobel Prize

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The 2009 Nobel Prize in Physiology or Medicine honored discovery of telomeres and telomerase by Elizabeth Blackburn, Carol Greider, and Jack Szostak. Their work explained how chromosome ends are protected and how telomerase counteracts telomere shortening, with major implications for aging and cancer. The discoveries resolved how complete replication of linear chromosomes is achieved.

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Tumor suppressor gene (TSG)

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A gene whose normal function restrains cell proliferation, promotes DNA repair, or triggers apoptosis, thereby preventing tumorigenesis. Inactivation or loss of TSGs contributes to cancer development and is often observed via mutations, deletions, or epigenetic silencing. The number of inactivated TSGs in tumors often exceeds activated oncogenes.

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Dominance of tumor phenotype

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When malignant cells are fused with normal cells, the resulting hybrid often loses tumorigenic capacity, indicating that normal cell functions can be dominant over malignant traits. However, some transformation modes (e.g., tumor viruses) can render hybrids tumorigenic, reflecting mechanistic differences in how malignancy is achieved. This observation supported the existence of recessive tumor suppressors.

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Retinoblastoma

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A pediatric eye tumor originating from precursor cells of the retina, occurring sporadically (usually unilateral) or in a familial bilateral form. Familial cases involve a germline mutation in the Rb gene and multiple tumors in both eyes, while sporadic cases require two somatic hits in a single cell. Rb loss predisposes to retinal tumors and, in carriers, to other cancers like osteosarcoma.

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Knudson two-hit hypothesis

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A model proposing that two inactivating events are required to eliminate both alleles of a recessive tumor suppressor gene and initiate tumor formation. Familial cases carry a germline first hit and require only one somatic second hit, explaining earlier onset and multiple tumors. The model was formulated from studies of retinoblastoma incidence patterns.

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Loss of heterozygosity (LOH)

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The somatic loss of the remaining wild-type allele in a cell that initially carried one mutated allele, resulting in hemizygosity or homozygosity for the mutated locus. LOH can occur via mitotic recombination, gene conversion, chromosomal deletion, or nondisjunction, and it is a common mechanism to inactivate tumor suppressor genes during tumorigenesis.

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Mitotic recombination

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An event during mitosis where homologous chromosomes exchange genetic material, potentially converting a heterozygous locus into homozygosity for a mutant allele. Mitotic recombination can produce LOH at frequencies higher than point mutation, providing a pathway for the second 'hit' in tumor suppressor inactivation. It is especially relevant in tissues with limited cell numbers.

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Gene conversion

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A DNA replication-associated process where a growing DNA strand temporarily uses a homologous chromosome as template and copies its sequence, potentially transferring a mutant allele to the sister chromatid. Gene conversion can create LOH without crossing over and is more frequent per cell generation than mitotic recombination. It contributes to somatic inactivation of tumor suppressors.

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Chromosomal deletion and nondisjunction

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Mechanisms that produce LOH by removing chromosomal regions or losing whole chromosomes. Deletion discards a chromosomal segment containing the wild-type allele, while nondisjunction during mitosis can yield loss of an entire chromosome followed by duplication of the mutant homolog. Both result in hemizygosity or homozygosity for mutant tumor suppressors.

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RFLP mapping

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Use of restriction fragment length polymorphisms (RFLPs) as genetic markers to track chromosomal regions that undergo LOH in tumors. Recurrent LOH at nearby markers suggested locations of unknown tumor suppressor genes, enabling positional cloning. RFLP analyses were an early tool to locate TSGs before dense SNP maps became available.

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SNP-based LOH detection

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PCR-based genotyping of single-nucleotide polymorphisms (SNPs) allows high-resolution mapping of LOH across the genome. Heterozygous SNP markers spaced frequently (about every 1 kb) in the human genome enable precise localization of deleted regions and candidate tumor suppressor loci. SNP analyses replaced RFLPs for finer mapping of LOH events.

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Promoter CpG methylation

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Addition of methyl groups to cytosines in CpG dinucleotides within gene promoters, which can repress transcription and silence tumor suppressor genes. Methylated CpGs recruit histone deacetylases and other chromatin modifiers, leading to compact chromatin and gene silencing. Epigenetic promoter methylation is a major alternative to mutation for inactivating TSGs in cancer.

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DNMT3B

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A DNA methyltransferase enzyme implicated in de novo CpG island methylation during tumorigenesis. Overexpression of DNMT3B in tumors like colon carcinomas causes hypermethylation and silencing of multiple tumor suppressor gene promoters. DNMT3B-mediated epigenetic changes contribute to cancer progression by shutting down protective genes.

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p16INK4A methylation

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Epigenetic silencing of the p16INK4A tumor suppressor by promoter methylation, commonly observed in bronchial epithelial cells of current and former smokers. Methylation of p16INK4A reduces its expression and cooperates with LOH to inactivate this key cell cycle regulator, increasing cancer risk in exposed populations. It exemplifies environmental influence on epigenetic TSG inactivation.

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p53

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A transcription factor and tumor suppressor that responds to diverse stresses by inducing cell-cycle arrest, DNA repair, senescence, or apoptosis. p53 activation preserves genome integrity and suppresses tumorigenesis; TP53 is the most frequently mutated gene in human cancers. Loss or mutation of p53 removes a critical cellular alarm system against oncogenic events.

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Mutant p53 dominance

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Many tumor-associated p53 missense mutants exert a dominant-negative effect by incorporating into p53 homotetramers and impairing DNA binding or transactivation. Because p53 functions as a tetramer, presence of even one mutant subunit can compromise the whole complex. This explains why some heterozygous p53 mutations have strong pro-tumorigenic effects.

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p53 activation pathways

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DNA damage and replication stress activate kinases (ATM/Chk2 for DSBs and ATR/Chk1 for ssDNA/stalled forks) that phosphorylate p53 and stabilize it by preventing Mdm2-mediated degradation. Stabilized p53 accumulates and transactivates target genes like p21 and pro-apoptotic factors, coordinating cell-cycle arrest and apoptosis. Multiple physiological stresses can elicit this pathway.

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Mdm2 negative feedback

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Mdm2 is an E3 ubiquitin ligase transcriptionally induced by p53 that binds p53, promotes its ubiquitylation, nuclear export, and proteasomal degradation. This forms a negative-feedback loop that keeps p53 levels low in unstressed cells and terminates p53 responses after damage resolution. Overexpression of MDM2 in tumors can functionally inactivate p53.

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p53 target genes

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Genes induced by p53 mediate cytostatic and pro-apoptotic outcomes, including CDK inhibitor p21 for cell-cycle arrest and TSP-1 (thrombospondin-1) to inhibit angiogenesis. p53-driven transcriptional programs coordinate DNA repair, senescence, apoptosis, and suppression of tumor-supporting processes like neovascularization. Loss of these targets contributes to tumor progression.

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Li-Fraumeni syndrome

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A hereditary cancer predisposition syndrome often caused by germline TP53 mutations, characterized by early onset and diverse tumor types including sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma. Affected families show high cancer incidence across many tissues, reflecting the central role of p53 in multiple cell types. Carriers develop multiple cancers at unusually young ages.

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Rb protein

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A pocket protein that restrains cell-cycle progression at the G1 R-point by binding and inhibiting E2F transcription factors when hypophosphorylated. Phosphorylation by CDK4/Cyclin D and CDK2/Cyclin E inactivates Rb, releasing E2F to induce S-phase genes. Loss or inactivation of Rb pathway components removes this proliferation checkpoint and contributes to tumorigenesis.

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R-point control

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A regulatory checkpoint in late G1 where the cell commits to DNA replication and division, controlled by the phosphorylation state of Rb and related pocket proteins. Signals promoting CDK activity hyperphosphorylate Rb and advance cells past the R-point, while inhibitors maintain hypophosphorylated Rb to block progression. Dysregulation of R-point controls is common in cancers.

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Id proteins and differentiation

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Id proteins lack a DNA-binding domain and act as dominant-negative inhibitors of lineage-specific bHLH transcription factors by sequestering their partners. Overexpression of Ids (sometimes induced by Myc) blocks differentiation; Rb normally sequesters Id proteins to permit differentiation. Excess Id relative to Rb contributes to dedifferentiation and tumor aggressiveness.

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APC

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A tumor suppressor mutated early in most colorectal cancers and in familial adenomatous polyposis (FAP); APC encodes a large scaffolding protein that regulates $\beta$-catenin degradation and cytoskeletal functions. Loss of APC leads to accumulation of nuclear $\beta$-catenin, constitutive Wnt pathway activation, stem-like proliferation in crypt cells, and chromosomal instability. APC also influences microtubules and cell motility.

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Wnt/$\beta$-catenin signaling

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A pathway where Wnt ligand binding to Frizzled/LRP receptors inhibits GSK-3$\beta$-mediated phosphorylation of $\beta$-catenin, preventing its degradation and allowing nuclear translocation. Nuclear $\beta$-catenin associates with Tcf/Lef transcription factors to drive genes that maintain stemness and proliferation. APC and the axin complex promote $\beta$-catenin degradation to terminate the signal.

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Chromosomal instability (CIN)

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A phenotype of increased rates of chromosome gains and losses in cells, often arising from defects in genes like APC that regulate mitotic spindle function or chromosome segregation. CIN produces karyotypic heterogeneity, fosters oncogenic evolution, and contributes to tumor progression and drug resistance. Loss of APC function is a known driver of CIN.

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VHL

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The von Hippel–Lindau tumor suppressor whose protein product pVHL recognizes hydroxylated prolines on HIF-1$\alpha$ under normoxia and targets it for ubiquitylation and proteasomal degradation. Loss of VHL stabilizes HIF-1$\alpha$, activating hypoxia-response genes (e.g., VEGF) that promote angiogenesis and metabolic adaptation, contributing to tumor development in VHL syndrome.

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HIF-1 regulation

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Under normoxia, proline hydroxylase enzymes hydroxylate HIF-1$\alpha$ prolines, enabling pVHL binding and ubiquitylation for degradation. In hypoxia, proline hydroxylases are inactive, HIF-1$\alpha$ accumulates, dimerizes with HIF-1$\beta$, and activates a transcriptional program that induces angiogenesis, glycolysis, and erythropoiesis. HIF targets include VEGF, PDGF, and TGF-$\alpha$.

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Neurofibromin (NF1)

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The protein encoded by NF1 functions as a Ras GTPase-activating protein (Ras-GAP) that accelerates conversion of Ras from the active GTP-bound state to the inactive GDP-bound state. Loss of neurofibromin elevates Ras signaling, driving proliferation and tumor formation such as neurofibromas and gliomas in neurofibromatosis type 1. NF1 has other poorly characterized domains that may contribute to its tumor suppressor role.