Cytoskeleton and Its Functions

Cytoskeleton

• Consists of microtubules, microfilaments (actin filaments), and intermediate filaments
• Microtubules: Largest filament type, composed of α-tubulin and β-tubulin subunits, approximately 25 nanometers in diameter. Assembled into linear protofilaments. Can rapidly grow or shrink in size due to polymerization or depolymerization, respectively.
• Microfilaments: Smallest filament type, composed of actin protein, around 8 nanometers in diameter. Common in muscle cells.
• Intermediate filaments: Composed of various protein subunits, around 10 nanometers in diameter. Associated with specific cell types (neurofilaments, desmin, keratins).

Functions of Cytoskeleton

• Maintains cell shape and resists deformation
• Transports intracellular cargo (e.g., vesicles)
• Facilitates cell movement and migration
• Aids in cell communication
• Assists in cell division.

Microtubules (Continued)

• Protofilaments (10-15 in number, 14 in mammalian cells) assemble to form a hollow cylinder, approximately 24 nanometers wide
• Contain y-tubulin, capping proteins, + and - ends to control growth

Motor Proteins

• Utilize ATP hydrolysis to generate movement and force
• Examples include kinesin (moves towards cell membrane), dynein (moves components inward), myosin (muscle contractions, cytokinesis, endocytosis, exocytosis)

Cell Division in Eukaryotes (Mitosis and Meiosis)

• Mitosis: Somatic cell division resulting in two genetically identical daughter cells. Involves 5 phases: Prophase, Prometaphase, Metaphase, Anaphase, and Telophase.
• Meiosis: Germ cell division, producing haploid gametes. Involves two rounds of cell division (Meiosis I and Meiosis II). Essential for sexual reproduction.

Regulation of Mitosis

• Cyclin-dependent kinases (CDKs) regulate the cell cycle, including the M phase.
• Kinases add phosphate groups to other molecules.
• CDKs are active only when associated with cyclin proteins. Cyclin concentration fluctuate

Regulation of Mitosis

• Cyclin-dependent kinases (CDKs) are crucial for accurate cell cycle progression. These enzymes add phosphate groups to other molecules (specifically, the amino acids serine, threonine, or tyrosine). CDKs are inactive unless bound to specific cyclin proteins, whose concentrations fluctuate throughout the cell cycle.

Mitosis (Stages)

• Prophase: Chromosomes condense, nuclear envelope breaks down, and the mitotic spindle begins to form.
• Prometaphase: Chromosomes attach to microtubules of the mitotic spindle.
• Metaphase: Chromosomes align along the metaphase plate (equatorial plane).
• Anaphase: Sister chromatids separate and move to opposite poles.
• Telophase: Chromosomes decondense, nuclear envelopes reform, and cytokinesis begins (division of cytoplasm).

Telophase and Cytokinesis

• Physical process completing the division of parent cell into two identical daughter cells.
• Signal for cytokinesis is the dephosphorylation of proteins, which are targets of CDKs.
• Cell membrane pinches in at the equator.
• Action of a contractile ring of actin and myosin filaments forms the cleavage furrow.

Meiosis (Stages)

• Prophase I: Homologous chromosomes pair up (synapsis), crossing over occurs (exchange of genetic material).
• Metaphase I: Homologous pairs (bivalents) line up at the metaphase plate.
• Anaphase I: Homologous chromosomes separate and move to opposite poles.
• Telophase I and Cytokinesis: Two haploid cells are formed.
• Meiosis II: Similar to mitosis, but with haploid cells. Sister chromatids separate, resulting in four haploid gametes.

Cell Division and Human Pathology

• Aneuploidy (abnormal chromosome number) is a common cause of human genetic disorders.
• Non-disjunction (failure of chromosomes to separate correctly) during meiosis is a major cause of aneuploidy. Examples include Down syndrome (trisomy 21).
• Mosaicism involves the presence of different cell populations within an individual, each with a different genetic makeup.

Chromosomes

• Chromosomes condense into compact structures during prophase.
• Condensins attach to chromosomes for compaction.
• Nuclear envelope disintegrates.
• Cohesins holds sister chromatids together.
• H3 and H1 histone phosphorylation are crucial for chromosome condensation and attachment.
• Centrosomes move to opposite poles to facilitate the process.
• Microtubule organizing centers (MTOCs) are essential structures, with the centrosome being the primary MTOC.
• Centrioles, duplicated during S phase, are part of the centrosome.
• Spindle fibers and microtubules are critical for chromosome alignment and movement during cell division.

Microtubules in Mitosis

• Astral microtubules position the mitotic spindle and orientation.
• Kinetochore microtubules attach to chromosomes; facilitate chromosome movement.
• Interpolar microtubules extend across the equator and have a sliding action to separate poles.

Motor Proteins in Mitosis

• Eg5 (Kinesin-5) is responsible for pole separation.
• Dynein performs pole focusing and transport.
• Chromokinesins (Kinesin-4, -10) facilitates ejection, and CENP-E helps transport chromosomes to the equator.

Mitochondrial Mosaicism

• Mitochondrial populations are heterogenous due to high mutation rate.
• Mitochondrial segregation occurs randomly during cell division.
• Variability in mitochondrial DNA (mtDNA) distribution in cells.

Tumorigenesis

• Tumor cells often possess genomic instability characterized by widespread DNA alterations, chromosome breaks, and aneuploidy.
• Aneuploidy can contribute to tumorigenesis by creating extra copies of oncogenes or deleting tumor suppressor genes.