11/18 NOTES

Sales Cycle Updates

• The sales cycle is ongoing, with focus on the balance and performance.

• Most students received higher scores on recent exams, indicating improved understanding.

Class Announcements

• Exams and lab reports were returned to students.

• Today marks the last lab of the semester unless makeup sessions are needed.

• No labs next week due to Thanksgiving. Makeup lab scheduled for December 2nd.

Upcoming Assignments and Events

• Perusal assignment due Tuesday night, covering apoptosis and the protein p53.

• Exam 6 scheduled for the Monday of Thanksgiving week.

Cell Cycle Overview

Checkpoints in the Cell Cycle

• Three critical checkpoints regulate the cell cycle:

  • G1 to S transition check

  • G2 to M checkpoint

  • Metaphase to Anaphase checkpoint

G2 to M Phase Checkpoint

• Criteria for passage:

  • Cell size (has it grown appropriately?)

  • DNA damage (must be repaired before division)

  • Complete DNA replication

Cyclin and CDK Mechanisms

• Cyclins regulate checkpoints, activating Cyclin-dependent Kinases (CDKs) when bound.

  • Activated mitotic cyclin-CDK complex triggers M phase entry by phosphorylating specific proteins (e.g. nuclear envelope breakdown, chromatin condensation).

• APC (Anaphase Promoting Complex) is crucial for progressing past the metaphase-anaphase checkpoint by targeting proteins for degradation.

• Cohesin degradation: Necessary for sister chromatids to separate. If active, separase degrades cohesin, allowing anaphase to occur.

G1 to S Phase Checkpoint

• Critical for assessing:

  • Growth factors (external signals required for cell growth)

  • Nutritional status (ensuring resources are available)

  • Cell size and DNA integrity (avoid copying damaged DNA)

• Activation of the CDK-cyclin complex is necessary for transitioning from G1 to S phase, with S cyclin triggering DNA replication protein synthesis.

Role of Growth Factors

Mechanism of Action

• Growth factors initiate the signaling cascade necessary for cell cycle progression:

  • Growth factors bind to RTKs (Receptor Tyrosine Kinases).

  • Activated RTKs undergo autophosphorylation, altering their conformation for downstream signaling.

  • The activation of Ras protein occurs, switching from GDP to GTP.

Proteins Involved in Signaling Cascade

1. RAS: Activated by binding GTP; initiates a series of kinase activations.

2. RAF: Activated by Ras, phosphorylates MEK.

3. MEK: Activated by RAF, phosphorylates MAPK.

4. MAPK: Moves to nucleus to phosphorylate transcription factors (ETS, Jun).

Cancer Connection

• Mutations in genes regulating the cell cycle can lead to uncontrolled growth and tumor formation.

• Constant activation of RAS leads to continuous cell cycle progression and uncontrolled replication, characteristic of cancerous cells.

Summary

• The complexities of cell cycle regulation underscore the importance of checkpoints and signaling pathways. Understanding these mechanisms is crucial for grasping cellular processes and their implications in health and disease.

Sales Cycle Updates

The sales cycle is currently ongoing, with a strong focus on assessing both the balance and performance of student learning outcomes. Extensive analysis of student performance indicates that a significant majority have achieved higher scores on recent exams, which strongly suggests a marked improvement in their overall understanding and retention of the subject matter.

Class Announcements

Exams and lab reports have been returned to all students, providing them with feedback for further improvement. Today also marks the last lab session of the semester unless there are any makeup sessions required due to student absences or scheduling conflicts. It is essential to note that there will be no lab sessions next week because of the Thanksgiving holiday; however, a makeup lab is scheduled for December 2nd to accommodate those who missed earlier sessions.

Upcoming Assignments and Events

Students should be reminded that a perusal assignment is due by Tuesday night. This assignment will specifically cover apoptosis and the role of the protein p53, which is critical in regulating the cell cycle and apoptosis. Exam 6 is scheduled for the Monday of Thanksgiving week, which will assess their understanding of recent topics discussed in class.

Cell Cycle Overview

Checkpoints in the Cell Cycle

Three critical checkpoints serve as regulatory mechanisms within the cell cycle:

• G1 to S Transition Check: This checkpoint ensures conditions are favorable for DNA synthesis.

• G2 to M Checkpoint: This checkpoint verifies that DNA replication has occurred correctly without damage.

• Metaphase to Anaphase Checkpoint: This checkpoint guarantees that all chromosomes are properly attached to the spindle apparatus before separation.

G2 to M Phase Checkpoint

Criteria for Passage:

• Cell Size: Must have grown adequately to support mitosis.

• DNA Damage: Any damage must be repaired prior to cell division.

• Complete DNA Replication: Ensures that all genetic material is intact before entry into mitosis.

Cyclin and CDK Mechanisms

Cyclins are crucial proteins that regulate the cell cycle checkpoints by activating Cyclin-dependent Kinases (CDKs) upon binding. The activated mitotic cyclin-CDK complex is responsible for triggering M phase entry through phosphorylation of specific proteins necessary for processes like nuclear envelope breakdown and chromatin condensation. The Anaphase Promoting Complex (APC) plays a pivotal role in progressing past the metaphase-anaphase checkpoint by targeting proteins, such as securin, for degradation.

• Cohesin Degradation: It is essential for the separation of sister chromatids. The enzyme separase becomes active when cohesin is degraded, facilitating the commencement of anaphase.

G1 to S Phase Checkpoint

This checkpoint is vital for assessing:

• Growth Factors: External signals that promote cell growth must be present.

• Nutritional Status: Resources must be sufficient to support cell division.

• Cell Size and DNA Integrity: Verification is necessary to avoid replicating damaged DNA.

The activation of the CDK-cyclin complex at this checkpoint is crucial for the transition from G1 to S phase, with S cyclin initiating the synthesis of proteins necessary for DNA replication.

Role of Growth Factors

Mechanism of Action

Growth factors start a signaling cascade that is critical for cell cycle progression:

• Binding to RTKs: Growth factors attach to Receptor Tyrosine Kinases (RTKs).

• Autophosphorylation: Activated RTKs undergo autophosphorylation, changing their conformation and enabling downstream signaling.

• Ras Activation: The Ras protein is activated and switches from GDP to GTP.

Proteins Involved in Signaling Cascade

• RAS: Becomes activated through GTP binding; initiates a kinase activation cascade.

• RAF: Activated by Ras, it subsequently phosphorylates MEK.

• MEK: Once activated by RAF, MEK phosphorylates MAPK.

• MAPK: Translocates to the nucleus to phosphorylate transcription factors like ETS and Jun, crucial for gene expression and cell proliferation.

Cancer Connection

Mutations in genes responsible for regulating the cell cycle can result in uncontrolled cellular growth and tumorigenesis. Constant activation of the Ras protein leads to persistent cell cycle progression and unregulated cellular replication, a hallmark of cancerous cells.

Summary

The intricate dynamics of cell cycle regulation highlight the essential nature of checkpoints and signaling pathways. A thorough understanding of these mechanisms is vital for comprehending cellular processes and their implications in both health and disease, particularly in the context of cancer biology and treatment strategies.