Cell Cycle Regulation Overview

Overview

This lecture covers the molecular regulation of the cell cycle, focusing on protein controls such as cyclins, CDKs, checkpoints, and tumor suppressors that ensure proper cell division.

Cell Cycle Phases and Checkpoints

• The cell cycle includes G1 (growth), S (DNA synthesis), G2 (growth), and M (mitosis/cytokinesis).
• There are three major checkpoints: G1 (nutrients/cell size/DNA damage), G2 (DNA damage), and M (chromosome attachment).
• Checkpoints pause the cycle to verify cell readiness before proceeding.

Cyclins and Cyclin-Dependent Kinases (CDKs)

• CDKs are enzymes that phosphorylate proteins but require cyclin binding for activity.
• CDKs are constantly present; cyclins cycle in concentration during the cell cycle.
• Cyclin levels rise and fall, regulating CDK activity and driving cell cycle progression.
• Ubiquitin tagging marks cyclins for destruction, causing CDK inactivation.
• Different cyclins (D, E, A, B) peak at specific cell cycle phases to control transitions.

Cyclin-CDK Complex Regulation

• The cyclin-CDK complex is regulated by phosphorylation: some sites activate, others inhibit.
• Active mitotic cyclin-CDK requires removal of inhibitory phosphates by phosphatases.
• This phosphorylation complexity ensures tight regulation of cell cycle events.

Anaphase Promoting Complex (APC)

• APC is a ubiquitin ligase that targets mitotic cyclins and securin for destruction.
• Securin degradation releases separase, which cleaves cohesin proteins holding sister chromatids together.
• APC activation requires CDC20, which is triggered only when all sister chromatids are attached to spindle fibers.
• Unattached kinetochores keep APC inactive via proteins like MAD and BUB, ensuring proper chromosome segregation.

DNA Replication Control in S Phase

• DNA replication must occur only once per cycle, regulated by origin (ori) licensing during G1.
• Pre-replication complex proteins bind ori in G1 and are phosphorylated in S to prevent re-binding.
• The protein geminin blocks re-assembly of the replication complex after initiation.

Tumor Suppressors: RB and p53

• Retinoblastoma protein (RB) inhibits S phase gene expression by sequestering E2F; phosphorylation of RB releases E2F for transcription.
• RB mutations can lead to uncontrolled S phase entry, contributing to cancer.
• p53 is activated by DNA damage and can induce cell cycle arrest or apoptosis by activating target genes like p21.
• ATM and ATR proteins detect DNA damage and promote p53 activation.

Key Terms & Definitions

• Cyclin — Regulatory protein whose concentration cycles and controls CDK activity.
• CDK (Cyclin-Dependent Kinase) — Enzyme that phosphorylates target proteins to regulate the cell cycle.
• Ubiquitin — Small protein that tags other proteins for degradation.
• Anaphase Promoting Complex (APC) — Ubiquitin ligase that ensures proper chromosome separation.
• Securin — Protein that inhibits separase; its degradation allows anaphase to proceed.
• Separase — Enzyme that cleaves cohesin to separate sister chromatids.
• Cohesin — Protein complex holding sister chromatids together.
• Origin of Replication (ori) — DNA site where replication begins.
• Geminin — Protein that prevents re-replication of DNA within the same cycle.
• RB (Retinoblastoma Protein) — Tumor suppressor that controls S phase entry.
• E2F — Transcription factor promoting S phase gene expression.
• p53 — Tumor suppressor that responds to DNA damage and can stop the cell cycle or trigger apoptosis.

Action Items / Next Steps

• Review the mechanisms of cyclin/CDK regulation and checkpoint controls.
• Be prepared to discuss the role of growth factors in cell cycle regulation in the next lecture.
• Read about apoptosis mechanisms in preparation for the next class.