p53 and Apoptosis: Cellular Response Mechanisms

p53: Guardian of Our Genome

• p53 is a key protein in a mammal's cellular response to stress
• It's synthesized in response to cellular stress
• Acts as a key player in how cells respond to daily stressors
• Manages the transcription factors necessary to synthesize proteins for stress response
• p53 activity is kept low by mdm2 prior to activation
• p53 must be phosphorylated and acetylated to become active
• Damaged DNA activates p53 through kinases and acetylases
• Activated p53 is released from mdm2 when DNA is damaged
• P53 can choose between apoptosis or DNA repair in response to DNA damage

Apoptosis: A Normal Occurrence

• Apoptosis is programmed cell death
• Characterized by cell and nucleus shrinkage, loss of adhesion to neighboring cells, blebs on the cell surface, and chromatin fragmentation
• p53 plays a role in deciding which cells undergo apoptosis
• Apoptosis is crucial for maintaining homeostasis by eliminating cells with irreparable DNA damage
• Apoptotic bodies, with phosphatidylserine on their surface, are recognized as "eat me" signals by macrophages
• Apoptosis occurs within less than an hour

Extrinsic Pathway of Apoptosis

• External stimuli initiate the process
• Ligand binds to the death receptor, activating the receptor
• Activated receptors bind to adaptor proteins (FADD and TRADD)
• These proteins interact with procaspase-8 to form a complex
• Caspase-8 is activated, initiating a cascade that leads to apoptosis

Intrinsic Pathway of Apoptosis

• Internal stimuli trigger this pathway
• Irreparable DNA damage, hypoxia, high cytosolic calcium, and severe oxidative stress activate the pathway
• Stressful stimuli activate Bax
• Bax moves from cytosol to the outer mitochondrial membrane
• Cytochrome c is released from mitochondria
• Cytochrome c, Apaf-1, and procaspase-9 interact to form the apoptosome
• Caspase-9 is activated and activates executioner caspases to carry out cell death

Free Radicals and Antioxidants

• Free radicals are highly reactive molecules with unpaired electrons
• Oxidative stress occurs when free radicals exceed the body's antioxidant capacity
• ROS (reactive oxygen species) are a general term for free radicals
• Oxidative stress can damage cells, leading to mutations and aging.

Dual Roles of ROS

• ROS play a role in cellular function
• Excessive ROS can damage cells and cause disease

Antioxidants Protect Cells

• Antioxidants protect cells against the harmful effects of free radicals
• Examples include vitamins A, C, E, beta-carotene, and lycopene.

Bcl2 Family

• Bax and Bcl2 are critical players in the intrinsic apoptotic pathway.
• If Bax is activated, it leads to apoptosis
• If Bcl2 is activated, apoptosis is blocked.

Cancer: Loss of Growth Control

• Cancer is characterized by uncontrolled growth, and loss of growth control due to altered DNA.
• Benign tumors may turn malignant with a chance of 50-50.

Telomerase

• Telomerase is an enzyme that adds new repeat units to the end of telomeres
• Repairs DNA ends at the telomere for cellular function
• Prevents shortening of telomeres in response to stress

Centromere and Telomere

• A central component of the kinetochore where spindle fibers attach to chromosomes
• Telomeres are protective structures at the ends of chromosomes, ensuring their stability.

Werner's Syndrome

• An inherited disease where individuals age prematurely due to telomere abnormalities.

Seemingly Immortal

• Cancer cells can divide indefinitely because of constant telomerase supply, and no normal cell aging process
• Preventing cell aging
• Cancer cells in stage 3 have spread but are still in the original site

Cancer Spread

• Cancer cells can enter the lymphatic system or vascular system, spreading to other parts of the body.

Genes in Carcinogenesis

• Tumor-suppressor genes prevent uncontrolled cell division and promote apoptosis.
• Oncogenes promote uncontrolled cell growth and stop apoptosis

Strategies for Combating Cancer

• Passive immunotherapy involves administering antibodies that target cancer cell surfaces.
• Active immunotherapy involves removing and stimulating immune cells in vitro before reintroducing them to patients
• Inhibiting activity of cancer-promoting proteins and inhibiting angiogenesis—a key strategy.

Live a Healthy Lifestyle

• Maintaining a healthy lifestyle, including a balanced diet, regular exercise, and stress management, is important for preventing cancer.

Explore the critical roles of p53 in cellular stress responses, including its function in apoptosis and DNA repair. This quiz covers the mechanisms by which p53 is activated and how it influences cell fate in the presence of DNA damage. Dive into the complexities of programmed cell death and its significance in maintaining cellular integrity.