Target type: biologicalprocess
A cellular senescence process associated with the dismantling of a cell as a response to oncogenic stress, such as the activation of the Ras oncogenic family. [GOC:BHF]
Oncogene-induced senescence (OIS) is a complex biological process that acts as a tumor suppressor mechanism. It involves the permanent cell cycle arrest of cells that have activated oncogenes, preventing their uncontrolled proliferation and tumor development. This process is initiated by various signaling pathways, often triggered by aberrant activation of oncogenes like Ras, Myc, or E2F.
Here's a detailed breakdown of the process:
1. **Oncogene Activation:** When an oncogene is activated, it disrupts normal cell cycle regulation, leading to increased proliferation and altered cellular functions. This can be due to mutations in the oncogene itself, overexpression, or aberrant signaling pathways.
2. **DNA Damage Response:** The activation of oncogenes can lead to DNA damage and genomic instability. This triggers a DNA damage response (DDR), a complex signaling cascade that aims to repair the damage. However, persistent oncogene activity can overwhelm the repair mechanisms, leading to accumulation of DNA damage.
3. **p53 Pathway Activation:** The DDR activates the p53 tumor suppressor pathway. p53 is a key transcription factor that controls cell cycle arrest, DNA repair, and apoptosis. Activation of p53 triggers the expression of genes involved in cell cycle arrest, including p21, which inhibits cyclin-dependent kinases (CDKs) required for cell cycle progression.
4. **Rb Pathway Activation:** The p53 pathway also activates the retinoblastoma (Rb) pathway, which further contributes to cell cycle arrest. Rb is a tumor suppressor protein that regulates the transcription of genes essential for cell cycle progression. When Rb is phosphorylated, it releases E2F transcription factors, which drive the expression of genes required for S phase entry. However, in OIS, p53 activates p16INK4a, which inhibits CDK4/6, preventing phosphorylation of Rb and keeping E2F inactive.
5. **Senescence-Associated Secretory Phenotype (SASP):** Senescent cells release a variety of signaling molecules, collectively known as the senescence-associated secretory phenotype (SASP). The SASP includes pro-inflammatory cytokines, chemokines, growth factors, and proteases. The SASP can have both beneficial and detrimental effects. On the one hand, it can promote immune surveillance and eliminate senescent cells. On the other hand, it can contribute to chronic inflammation and aging-related diseases.
6. **Permanent Cell Cycle Arrest:** The combination of p53 and Rb pathway activation, along with the SASP, leads to a permanent cell cycle arrest in the G1 phase. Senescent cells adopt a distinct morphology, often showing enlarged and flattened morphology with increased lysosomal activity. They also display increased senescence-associated β-galactosidase (SA-β-gal) activity, a marker of senescence.
Overall, OIS is a crucial tumor suppressor mechanism that prevents the proliferation of cells with activated oncogenes. However, the SASP associated with senescent cells can have complex effects on surrounding tissues and contribute to aging-related pathologies. The balance between the beneficial and detrimental effects of OIS is an active area of research.'
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Protein | Definition | Taxonomy |
---|---|---|
GTPase HRas | A GTPase HRas that is encoded in the genome of human. [PRO:DNx, UniProtKB:P01112] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
stallimycin | |||
lonafarnib | lonafarnib : A 4-{2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl}piperidine-1-carboxamide that has R configuration. It is used as oral farnesyltransferase inhibitor. lonafarnib: inhibitor of farnesyl protein transferase | 4-{2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl}piperidine-1-carboxamide | antineoplastic agent; EC 2.5.1.58 (protein farnesyltransferase) inhibitor |
l 778,123 | L-778,123 (free base) : A member of the class of imidazoles that is 1H-imidazole substituted by (4-cyanophenyl)methyl and [4-(3-chlorophenyl)-3-oxopiperazin-1-yl]methyl groups at positions 1 and 5, respectively. It is a dual inhibitor of FPTase and GGPTase-I. | imidazoles; monochlorobenzenes; nitrile; piperazinone; tertiary amino compound | antineoplastic agent; EC 2.5.1.58 (protein farnesyltransferase) inhibitor; EC 2.5.1.59 (protein geranylgeranyltransferase type I) inhibitor |
bms 214662 | 7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine: a farnesyltransferase inhibitor; structure in first source BMS-214662 : A member of the class of benzodiazepines that is 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine substituted by (1H-imidazol-5-yl)methyl, benzyl, (thiophen-2-yl)sulfonyl, and cyano groups at positions 1, 3R, 4 and 7, respectively. It is a potent inhibitor of farnesyltransferase (IC50 = 1.35nM) which was under clinical development for the treatment of solid tumors. | benzenes; benzodiazepine; imidazoles; nitrile; sulfonamide; thiophenes | antineoplastic agent; apoptosis inducer; EC 2.5.1.58 (protein farnesyltransferase) inhibitor |