11/20 CELL SIGNALING

Class Announcements

• Importance of attendance: Class participation improves learning

• Update on cancer lab: Analysis due by Sunday.

• Thanksgiving week: No lab scheduled.

• Makeup lab: For students who missed previous labs; an email has been sent to those affected.

• Upcoming exam: 6th exam in 5 days.

Cell Signaling Pathways Overview

Bowel Signaling Pathway

• Inactive State of Proteins: Before growth factors bind, key proteins (RAS, MEK, MAPK, adapter proteins, receptor tyrosine kinases) are inactive.

• Activation Process:

  • Growth factors bind to receptor tyrosine kinases (RTKs).

  • RTKs dimerize and become autophosphorylated, changing confirmation.

  • The adapter protein connects to the RTK, activating RAS by replacing GDP with GTP.

• Activation of the Kinase Cascade:

  • Activated RAS binds to RAF; activates RAF kinase.

  • RAF phosphorylates and activates MEK.

  • MEK phosphorylates MAPK, leading MAPK into the nucleus.

  • MAPK phosphorylates transcription factors (ETS and Jun), driving cell cycle progression.

G1 to S Phase Transition

Cyclin Activation

• G1/S Cyclin Production:

  • The cyclin binds to and activates CDK (Cyclin-dependent Kinase).

• RB Protein Interaction:

  • Activated CDK phosphorylates RB protein, changing its confirmation.

  • Phosphorylated RB no longer inhibits E2F, facilitating transcription of proteins necessary for S phase, including helicase, DNA polymerases, etc.

Role of E2F and Cyclins

• E2F becomes activated to promote DNA replication machinery once unbound from RB.

• Inactivated RB enhances transcription processes necessary for DNA synthesis.

Cancer Mechanisms

Mutations and Cancer Development

• Mutations in DNA can alter protein structures, changing their functions.

• Cancer typically results from accumulative genetic mutations affecting cell cycle regulation.

• RAS mutation found in 30% of cancers, highlighting the critical role of RAS in signaling pathways.

Checkpoints in the Cell Cycle

• Importance of checkpoints: They ensure cells only progress when conditions are favorable.

• Each checkpoint involves specific protein interactions and regulations.

• Mutations can disrupt this regulation, leading cells to proceed through the cycle erroneously.

Experimental Activity

• Students represent different proteins involved in cell signaling (G1 to S phase).

• Activation and inactivation of proteins simulated through movement and interaction among student volunteers.

• Reinforces understanding of protein roles in the signaling pathways.

Summary of Key Concepts

Oncogenes vs. Tumor Suppressor Genes

• Oncogenes: Promote cell cycle progression (e.g., RTKs, RAS, Cyclins).

  • In their normal state, they're referred to as proto-oncogenes.

• Tumor Suppressor Genes: Inhibit cell cycle progression (e.g., RB protein).

  • Mutations can render tumor suppressors inactive, allowing unregulated cell growth.

  • Accumulation of mutations in oncogenes and tumor suppressor genes leads to cancer.

Importance of Apoptosis

• Apoptosis removes damaged or mutated cells, preventing the propagation of defects.

• Failure in apoptosis can lead to continuous mutation cycles in daughter cells.

• The interplay between apoptosis and cancer highlights the roles of genes like p53.

Conclusion

• Continuous monitoring of mutation accumulation is crucial for understanding cancer progression.

• Discussion on apoptosis and tumor suppressor roles to continue in the next class.

Class Announcements

• Importance of Attendance: Regular class participation is crucial as it enhances learning opportunities and fosters a collaborative educational environment. Engaging in discussions and practical activities can significantly improve comprehension of complex subjects.

• Update on Cancer Lab: Students are reminded that the analysis for the cancer lab is due by Sunday at 5 PM. Ensure to follow the specific guidelines provided in the lab manual to meet the assessment criteria.

• Thanksgiving Week: There will be no lab sessions scheduled during Thanksgiving week, allowing students to focus on their studies or spend time with family.

• Makeup Lab: A makeup lab has been organized for students who missed previous lab sessions. A detailed email has already been sent to those affected, outlining the schedule and expectations for the makeup lab.

• Upcoming Exam: An important reminder for students that the 6th exam is in just 5 days. It will cover all topics discussed in class thus far, including but not limited to cell signaling pathways, mechanisms of cancer, and the role of various proteins in these processes.

Cell Signaling Pathways Overview

• Bowel Signaling Pathway

  • Inactive State of Proteins: In the unactivated state, key proteins (including RAS, MEK, MAPK, and receptor tyrosine kinases [RTKs]) remain inactive and are crucial in regulating various cell functions and fate.

  • Activation Process:

    • Binding of growth factors to receptor tyrosine kinases (RTKs) leads to their activation.

    • Once RTKs dimerize and undergo autophosphorylation, this conformational change initiates a signaling cascade.

    • An adapter protein connects to the activated RTK, facilitating the exchange of GDP for GTP on RAS, prompting its activation.

  • Activation of the Kinase Cascade:

    • The activated RAS protein binds to RAF, initiating the activation of RAF kinase.

    • Activated RAF subsequently phosphorylates and activates MEK.

    • The activation of MEK leads to the phosphorylation of MAPK, which then translocates into the nucleus.

    • Within the nucleus, MAPK phosphorylates key transcription factors (such as ETS and Jun), promoting genes vital for cell cycle progression.

• G1 to S Phase Transition

  • Cyclin Activation

    • G1/S Cyclin Production:

      • Specific cyclins bind to and activate Cyclin-dependent Kinase (CDK), critical for driving progression from G1 to S phase.

    • RB Protein Interaction:

      • Activated CDK phosphorylates the RB protein, leading to a conformational change that inactivates RB.

      • In its phosphorylated state, RB relinquishes its inhibition on E2F, a transcription factor necessary for synthesizing proteins essential for DNA synthesis.

• Role of E2F and Cyclins

  • E2F becomes active after its release from RB and is essential in stimulating the transcription of genes required for DNA replication, such as helicases and DNA polymerases.

  • The inactivation of RB thus facilitates robust transcriptional responses necessary for the initiation of DNA synthesis, illustrating a key regulatory mechanism of the cell cycle.

Cancer Mechanisms

• Mutations and Cancer Development

  • Mutations in cellular DNA can lead to changes in protein structure and function, which may disrupt normal cellular processes. Cancer is often the result of an accumulation of genetic mutations that affect cell cycle regulation and cellular proliferation.

  • Notably, RAS mutations are present in approximately 30% of all cancers, underscoring the critical role that RAS and its downstream signaling pathways play in tumorigenesis.

• Checkpoints in the Cell Cycle

  • Importance of Checkpoints: Checkpoints serve as critical control mechanisms within the cell cycle, ensuring that cells only proceed to the next phase when conditions are favorable and any DNA damage is repaired.

  • Specific protein interactions and regulatory mechanisms govern each checkpoint, with disruptions due to mutations leading to unchecked cellular proliferation and potential tumorigenesis.

Experimental Activity

• Students engage in a hands-on activity where they embody various proteins involved in cell signaling from the G1 to S phase. This interactive simulation allows them to better grasp how activation and inactivation of these proteins occur through physical movement and role-playing, enhancing their understanding of signaling pathways through experiential learning.

Summary of Key Concepts

• Oncogenes vs. Tumor Suppressor Genes

  • Oncogenes: Genes that promote cell cycle progression (e.g., RTKs, RAS, Cyclins). These genes, when mutated, can become oncogenic, leading to uncontrolled cell growth. Their normal counterparts are referred to as proto-oncogenes.

  • Tumor Suppressor Genes: Genes that inhibit cell cycle progression (e.g., RB protein). Mutations in tumor suppressor genes can inactivate their functions, resulting in the potential for unregulated cell division. The accumulation of mutations in both oncogenes and tumor suppressor genes is a hallmark of cancer development.

• Importance of Apoptosis

  • Apoptosis is a critical process that eliminates damaged or mutated cells from the population, thereby preventing the propagation of deleterious genetic defects. Failures in the apoptotic process can result in endless cycles of mutations in daughter cells, contributing to cancer development.

  • The relationship between apoptosis and cancer underscores the significance of genes like p53, which play roles in regulating both cellular repair and programmed cell death.

Conclusion

• Continuous monitoring of mutation accumulation in cells is essential for comprehending the complexities of cancer progression. Discussions regarding the roles of apoptosis and tumor suppressor functions will be explored further in the next class, emphasizing their contributions to maintaining cellular integrity and preventing tumor development.