Table 6-7 Molecular-Stress Response and Checkpoint Pathways (see Appendix C for illustrations)

Checkpoint Pathways

Function and Cell Response

G1/S checkpoint

Monitors nutritional state, biosynthetic capacity, and cell adhesion and imposes G1 arrest until cell is prepared for S phase.

G2/M checkpoint

Monitors completion of DNA synthesis (S phase) and imposes G2 arrest until cell is prepared for M phase.

Metaphase/anaphase checkpoint

Monitors attachment of chromosomes to the spindle and imposes metaphase arrest until cell is ready for anaphase.

Molecular-Stress Response Pathways

Function and Cell Response

DNA damage (genotoxic stress)

Kinases are activated at DNA damage site by single stranded DNA and 5′, 3′ ends, leading to p53 activation and transcription of genes encoding p21 inhibitors of cyclin-dependent kinases, and hence G1/S or G2/M arrest until repair is complete.

Cytosolic unfolded protein pathway

Activated by heat, alcohol, anaerobiosis, and amino acid analogs, leading to activated transcription of genes encoding chaperone proteins until protein refolding is complete.

Endoplasmic reticulum (ER) unfolded protein pathway

Unfolded proteins activate receptor thre/seri kinase, leading to release of a nuclease that degrades some mRNAs and reduces translation (G1 arrest), and splices some mRNAs leading to transcription of genes encoding chaperone proteins until protein refolding is complete.

Apoptosis (cell death)

Triggered by intracellular damage or extracellular signals, leading to caspase protease activation and cell destruction.

Ultraviolet, hyperosmotic shock, free-radical oxidation pathways

Mediated by MAP kinases, leading to transcription, until damage is reversed.

Note: Many of these are found in single-celled eukaryotes as well as in most or all cells of animals.

cants. Broadly acting toxicants are likely to show up as triggers of stress responses.

  • The intercellular signaling pathways of metazoa probably arose in evolution as elaborations and reworkings of the more ancient molecular-stress and checkpoint pathways of single-celled eukaryotic ancestors. This is surmised because a number of the intermediates (e.g., protein kinases) of the molecular-stress and checkpoint pathways are also used in the metazoan signaling pathways.

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