Fundamentals of Cell Biology

1. Fundamentals of Cell Biology Chapter 12: Control of Gene Expression

2. Chapter Summary: The Big Picture (1) • Chapter foci: • How the key nuclear signaling proteins enter the nucleus • How DNA binding proteins (the effectors of nuclear signaling pathways) function to control gene expression • How changes in gene expression result in changes in signaling pathways

3. Chapter Summary: The Big Picture (2) • Section topics: • Many signaling proteins enter the nucleus • Effector proteins in the nucleus are grouped into three classes

4. Many signaling proteins enter the nucleus • Key Concepts (1): • Numerous classes of cytosolic signaling proteins routinely pass into and out of the nucleus. • Proteins that bind to membrane-soluble signaling molecules move directly into the nucleus and function as transcription factors. • Some plasma membrane-associated signaling proteins and protein fragments enter the nucleus, but their function in the nucleus is not well understood. .

5. Many signaling proteins enter the nucleus • Key Concepts (2): • Nuclear signaling proteins that do not bind DNA regulate proteins that do. • The same regulatory mechanisms that control cytosolic signaling proteins control nuclear signaling proteins; phosphorylation/dephosphorylation is the best understood nuclear regulatory mechanism.

6. Nuclear receptors translocate from the cytosol to the nucleus during signaling • Notch is a transmembrane scaffold receptor that enters the nucleus Figure 12.02: Notch is a cell surface receptor that signals in the nucleus.

7. G-protein coupled receptors and GPCR fragments signal in the nucleus Table 12.01: GPCRs found in the nucleus. Figure 12.03: DFZ2 is a GPCR that signals in the nucleus.

8. Receptor protein tyrosine kinases signal in the nucleus Figure 12.04: Ryk is a tyrosine kinase receptor that signals in the nucleus.

9. Some protein kinases phosphorylate nuclear proteins Figure 12.06: Protein Kinase B signals in the nucleus. Figure 12.05: MSKs transmit MAP kinase signals in the nucleus.

10. PKC signals in both the cytosol and nucleus

11. Other signaling molecules in the nucleus • PTEN is a nuclear phosphatase • An ATP-binding calcium ion channel is present in the plasma membrane and nuclear envelope in some neurons • Adenylyl cyclases are present in the nucleus

12. Effector proteins in the nucleus are grouped into three classes • Key Concepts (1): • Cohesins hold two DNA strands together by forming a ring-shaped complex around them. • Condensins form a ring-shaped structure that gathers loops of DNA together. • Histones are phosphorylated by a number of protein kinases; histone phosphatases remove them. This modification of histones is critical for permitting gene expression.

13. Effector proteins in the nucleus are grouped into three classes • Key Concepts (2): • Histone acetyltransferases add acetyl groups to histones, thereby loosening their interaction with the DNA surrounding nucleosomes. This loosening activates the neighboring DNA by promoting expression of genes in this area. Histone deactylases remove the acetyl groups. • Histone methylation creates a binding site for heterochromatin proteins and promotes DNA silencing.

14. Effector proteins in the nucleus are grouped into three classes • Key Concepts (3): • Histone ubiquitination can either promote transcription or trigger histone degradation, depending on number of ubiquitin proteins added to each histone. • General transcription factors assemble at the core promoter and serve as the foundation for RNA polymerase activation. • Activator and repressor proteins are transcription factors that control the activity of the general transcription complex. Some activators bind to enhancer sequences located hundreds of base pairs away from the core promoter.

15. Cohesins and condensins help control the packaging state of chromatin Figure 12.07: Cohesins and condensins control the spatial arrangement of chromatin.

16. Histone modifiers control the structure of nucleosomes Figure 12.09: Histone modifications on the nucleosome core particle. Most modified sites in histones have a single, specific type of modification, but some sites can have more than one type of modification. Figure 12.08: Chromatin modeling is modification of histones to permit their removal or sliding along a piece of DNA.

17. Acetylation of histones Figure 12.10: The N-terminal tails of histones H3 and H4 can be acetylated, methylated, or phosphorylated at several positions. Figure 12.11: Acetylation associated with gene activation occurs by directly modifying specific sites on histones that are already incorporated into nucleosomes.

18. Transcription factors promote the expression of genes Figure 12.12: Regulatory regions controlling a gene transcribed by RNA polymerase II. Figure 12.13: The sequential assembly of the general transcription complex for a gene transcribed by RNA pol II.

19. How do these proteins find and bind to this particular region of DNA? Figure 12.15: Two views of a leucine zipper. Figure 12.14: Two views of a zinc finger DNA binding motif.

20. Enhancer sequences bind activators at a distance from the promoter Figure 12.16: Mediator helps form an enormous protein complex near the transcription start site.

21. Signal transduction pathways and gene expression programs form feedback loops Figure 12.17: Examples of positive and negative feedback loops in signal/gene expression pathways. Figure 12.18: ERK is a decision-making protein.