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#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

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

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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

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

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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

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

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