Table of Contents
Definition / generalCite this page: Pernick N. Cell cycle. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainscell.html. Accessed January 20th, 2021.
Definition / general
- In non-neoplastic cells, is controlled by proteins that intervene at checkpoints to prevent progression to next phase
- Enzymatic activity of protein is activated by phosphorylation, which changes their conformation, and usually leads to more phosphorylation (or kinase) activity
- Phosphorylation also creates docking sites on phosphorylated proteins, especially with tyrosine kinases, which recruits other target proteins
- Cell cycle: G1 to S (DNA synthesis) to G2 to M (mitosis)
- Cells NOT in the cell cycle (in resting phase) are in G0
G1
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- pRb (retinoblastoma protein) binds to E2F (transcription factor), which blocks transcription of S phase genes; cells stimulated by extracellular signals cause accumulation of CDK 4-6/cyclin D1 complex, which phosphorylates Rb, reducing its affinity for E2F, causing pRb to dissociate, freeing E2F to activate S phase genes
- Ubiquitin, in response to unknown stimulus, binds to and destroys CDK inhibitors, making CDK active
- p16 gene (CDKN2) inhibits CDK4-6/cyclin D1 complex, which prevents phosphorylation of Rb, which prevents progression of cell cycle into S phase
S
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- Growth factor binds to receptor on outer membrane
- Receptor on inner membrane dimerizes, which activates tyrosine or serine/threonine kinases
- Dimerized receptor subunits phosphorylate each other on tyrosine residues, creating docking sites for other proteins
- Grb2, an adaptor molecule which transfers the activation state, docks to phosphotyrosine and attracts the Sos protein
- Sos, a nucleotide exchange factor, attracts Ras
- Ras binds to inner membrane by linking to an isoprenyl group (farnesyl): process is called prenylation
- Ras binds GTP and becomes activated
- Activated Ras is a kinase, which activates Raf-1 via GTP
- Somehow Raf-1 is translocated from cytosol to plasma membrane
- Ras is inactivated by GAP (GTPase activating protein), which increases Ras's intrinsic GTPase activity
- Activated Raf-1 is a kinase, which activates MEK
- MEK activates MAPK/ERK (mitogen activated protein kinase / extracellular signal regulated kinase) using ATP
- Activated MAPK/ERK directly activates:
- ERK1/2 (extracellular signal regulated protein kinases 1 and 2)
- BAD (bcl2 family) by phosphorylation
- Ribosomal S6 protein kinase (RSK = pp90rsk), which translocates to nucleus and phosphorylates several transcription factors, including jun
- Transcription factors (fos)
- (Alternate pathway) CREB kinase, which phosphorylates and activates CREB at serine 133, which activates intermediate early growth and some delayed response genes with CREB binding sites
- Activated MAPK also translocates to nucleus, where it phosphorylates and activates transcription factor ELK1 at Ser 383
- ELK1, with serum response factor, binds to serum response element within IEG promoter to activate IEG genes
- Activated fos and jun bind near myc gene, which initiates gene transcription
- Activated myc activates other genes, including cyclin D1
- Cyclin D1 may initiate progression of cells from S
G2
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- M phase promoting factor (MPF) is CDC2 protein kinase plus cyclin B
- MPF is inactive when Threonine 14 & Tyrosine 15 are phosphorylated (by Wee1 and Myt1 kinases)
- Plx1 extensively phosphorylates CDC25 at mitosis, which activates it
- Activated CDC25 dephosphorylates Thr14 & Tyr15 (antagonistic to Wee1 & Myt1), which activates CDC2
M
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- Cyclin levels increase
- Increased cyclin partially activates CDK (cyclin dependent kinase), which has bound inhibitors
- CDK triggers beginning of mitosis (prophase, metaphase)
- Ubiquitin is passed from enzymes E1 to E2 to E3 (bucket brigade)
- E2: active throughout cell cycle
- E3: temporal specificity; is on mitotic spindle, checks if all chromosomes are on spindle.
- If so, ubiquitin tags an unknown "tether" protein for proteolysis, which causes anaphase to proceed
- Ubiquitin tags cyclin for proteolysis, which inactivates CDK, and allows mitosis to finish