Skip to content
Login Register

#cell cycle control

3 public questions tagged with this topic.

Cell Cycle Regulation

What is the role of Wee1 kinase in CDK regulation?

G2/M commitment governed by antagonism between inhibitory Wee1/Myt1 kinases and activating Cdc25 phosphatases acting on CDK1-Cyclin B. Wee1 encodes nuclear tyrosine kinase belonging to WEE family capable of phosphorylating both threonine and tyrosine. Active during S and G2 phases, Wee1 phosphorylates CDK1 at conserved glycine rich loop residues Thr14 and Tyr15 positioned near ATP binding cleft. These phosphates sterically hinder ATP orientation and substrate catalysis maintaining low activity even though cyclin B accumulates to high levels, effectively preventing premature mitotic entry while replication completes. Inhibition reinforced by Myt1 membrane associated kinase adding Thr14 modification. At mitotic threshold, rising Plk1 and CDK1 phosphorylate Wee1 creating phosphodegron recognized by SCF-betaTrCP ligase for ubiquitination and degradation plus nuclear export, while concurrently activating Cdc25C. Cdc25 removes Thr14/Tyr15 phosphates reversing inhibition. DNA damage checkpoint activates Chk1 which phosphorylates Cdc25 isoforms causing 14-3-3 sequestration and stabilizes Wee1 to enforce G2 arrest. Pharmacological Wee1 inhibitors like adavosertib force premature mitosis in cancer cells with accumulated damage causing mitotic catastrophe. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Morgan, Cell Cycle Control: Wee1 Regulation of CDK1, Principles of Control, Chapter 3; Mueller et al., Wee1 Kinase in DNA Damage G2 Checkpoint.

View Details
Cell Cycle Regulation

The phosphorylation of CDK at Thr-160 by CAK leads to:

CDK activation involves multiple ordered modifications ensuring integration of multiple regulatory inputs. Monomeric CDK presents T-loop obstructing peptide substrate binding and PSTAIRE helix oriented outward preventing coordination of ATP phosphates. Cyclin association through extensive hydrophobic interface rotates PSTAIRE helix inward aligning Glu51 with Lys33 for ATP positioning and partially displaces T-loop. However maximal substrate affinity requires phosphorylation of conserved threonine within T-loop, Thr160 in CDK2, Thr161 in CDK1, Thr172 in CDK4, catalyzed by CDK-activating kinase complex composed of CDK7, Cyclin H and assembly factor MAT1 part of transcription factor TFIIH. Phospho-threonine coordinates network of three arginine residues Arg50 Arg126 Arg150 creating stable beta-sheet platform for peptide binding increasing affinity hundredfold and aligning catalytic aspartate Asp145 for phosphotransfer. Dephosphorylation of inhibitory Thr14 Tyr15 by Cdc25 family further required for full activity. CAK activity largely constitutive linking cell cycle progression to transcriptional capacity, yet cyclin availability limits timing. Structural studies by Pavletich reveal stabilization mechanism explaining how Thr160 phosphorylation boosts catalytic efficiency and substrate recruitment during cell cycle transitions.

Ref: Fisher & Morgan, CAK Phosphorylation of CDK at Thr160 and Activation Mechanism, Cell 1994; Alberts et al., Chapter 17, CDK Activation Steps.

View Details
Cell Cycle Regulation

What happens if p53 is mutated?

Functional p53 integrates stress signals, including DNA damage, oncogene activation, and hypoxia, to decide between cell cycle arrest, senescence, or apoptosis. Under normal conditions, wild-type p53 accumulates after ATM phosphorylates serine 15 and CHK2 phosphorylates serine 20, displacing E3 ubiquitin ligase MDM2 that normally targets p53 for proteasomal degradation. Transcriptional program includes CDKN1A encoding p21 inhibitor of CDK2-cyclin E and CDK4-cyclin D, causing Rb to remain hypophosphorylated and E2F-dependent S-phase entry genes repressed, imposing G1 arrest to allow repair. If TP53 gene is mutated, common missense mutations in DNA-binding domain producing dominant-negative tetramers, cells lose ability to transactivate p21 and other checkpoint targets, so G1 arrest fails despite DNA damage. Damaged templates proceed into replication, accumulating mutations and chromosomal aberrations driving tumor progression. Mutant p53 does not accelerate apoptosis or permanently block CDK1; instead it disables G1 surveillance and also compromises apoptosis via BAX and PUMA reduction. Consequently, p53 mutation abolishes G1 checkpoint stringency and genomic stability, explaining high prevalence in cancers.

Ref: Vogelstein et al., Nature 2000, Surfing p53 Network; Levine & Oren, Nature Rev Cancer 2009, p53 Mutations.

View Details