Cell membranes consist of a lipid bilayer and associated proteins and carbohydrates. In the bilayer, the hydrophilic portions of the lipids are arranged on the external and cytosolic surfaces, and the hydrophobic tails are located in the interior. Transmembrane proteins are anchored to the core of the bi-layer by their hydrophobic
regions and can be removed only by detergents that disrupt the bi-layer. Peripheral membrane proteins are attached to the surface of the membrane by weak electrostatic forces and are easy to remove by altering the pH or ionic strength of their environment.
CYTOPLASM AND CELL ORGANELLES :
The Cytoplasm is a dynamic fluid environment bounded by the cell membrane. It contains various membrane-bound organelles, nonmembranous structures (such as lipid droplets, glycogen, and pigment granules), and structural or cytoskeletal proteins in either a soluble or insoluble form. The endoplasmic reticulum (ER) is a continuous tubular meshwork that may be either smooth (SER) or rough (RER) were studded with ribosomes. RER is involved in protein synthesis while the SER is involved in steroid synthesis and detoxification. The discoid stacks (CGN, cis, medial, trans, and TGN as one moves from the RER-side to the secretory vesicle-side) of the Golgi apparatus are involved in packaging and routing proteins for export or delivery to other organelles, including lysosomes and peroxisomes. Lysosomes degrade intracellular and imported debris, and peroxisomes oxidize a variety of substrates, through beta-oxidation and are the sole source of plasmalogens. Targeting sequences include KDEL, which targets ER proteins from the Golgi to the ER, and mannose 6-phosphate, which targets proteins to the lysosome. Mannose 6-phosphate receptors are found in the Golgi and lysosomes. In the absence of mannose 6phosphate on lysosomal enzymes (I-cell disease) they follow the default pathway and are secreted from the cell. Lysosomal enzymes are specific for the substrate; the absence of specific enzymes results in lysosomal storage diseases such as Tay-Sachs. Secretory granules leave the TGN to dock with the plasma membrane. In that process, v-SNARE on the vesicle docks with t-SNARE on the cell membrane and requires Rab GTPase-activity, linking to tethering proteins, and eventually to a receptor protein in the cell membrane. Receptor-mediated endocytosis is the process that permits the selective uptake of molecules into the cell using clathrin-coated pits and vesicles. Molecules not recycled to the cell membrane enter early endosomes and subsequently late endosomes by way of multivesicular bodies (MVBs). The late endosome is more acidic than the early endosome and generally leads to the degradation of the molecules in lysosomes. There are several major pathways for the shuttling of receptors and ligands.
• The internalized ligand-receptor complex dissociates in the early endosome with the recycling of receptors [e.g., low density-lipoprotein (LDL)LDL-receptor complex].
• Receptor and ligand are recycled (e.g., iron-transferrin-transferrin receptor complex).
• The internalized ligand-receptor complex dissociates in the late endosome and is degraded in the lysosome (e.g., growth factors such as epidermal growth factor).
• Internalized ligand-receptor passes through the cell (transcytosis) and is released at another surface (e.g., IgA uptake by small intestinal enterocytes).
Only the nucleus, which is the repository of the genetic information stored in deoxyribonucleic acid (DNA), and the mitochondria, which are the storage sites of energy for cellular function in the form of adenosine triphosphate (ATP), are enclosed in double membranes. Also included in the cytoplasm are three classes of proteins that form the cytoskeletal infrastructure: actin bundles that determine the shape of the cell; intermediate filaments that stabilize the cell membrane and cytoplasmic contents; and microtubules (tubulin), which use molecular motors (i.e., dynein and kinesin) to move organelles within the cell.
NUCLEUS :
The nucleus consists of nuclear envelope that is continuous with the ER, chromatin, matrix, and a nucleolus the site of ribosomal ribonucleic acid (rRNA) synthesis and initial ribosomal assembly. The nuclear envelope contains pores for bidirectional transport and is supported by intermediate filament proteins, the lamins. Chromatin consists of euchromatin (eu = true), which is an open form of DNA that is actively transcribed, and heterochromatin that is quiescent. There is a sequential packing of chromatin beginning with the DNA double helix, which is combined with histones to form the nucleosomes, the smallest unit of chromatin structure. This is the “beads on a string” structure with the histones forming the octamer arrangement of paired H2A, H2B, H3, and H4. H1 is the linker histone. The nucleosomes are connected by strands of protein-free DNA, so-called linker DNA. Nucleases degrade the linker DNA, but nucleosome particles are protected against micrococcal nuclease activity because of the close interaction of DNA with histone proteins. The next orders of packing are the 30 nm chromatin fibril, the chromatin fiber with loops of chromatin fibrils, and chromatin fibers loosely or tightly packed in euchromatin and heterochromatin respectively. During cell division, DNA is accurately replicated and divided equally between two daughter nuclei. Equal distribution of chromosomes is accomplished by the microtubules of the mitotic spindle. The separation of cytoplasm (cytokinesis) occurs through the action of an actin contractile ring. The cell cycle consists of interphase (G1, S, and G2), and the stages of mitosis (M): prophase, prometaphase, metaphase, anaphase, and telophase. The cell cycle is regulated at the G1/S and G2/M boundaries (checkpoints) by phosphorylation of complexes of a protein kinase [cyclin-dependent kinase (Cdk) protein] and a cyclin (cytoplasmic oscillator). For example, the G2/M interface is regulated by the M-Cdk complex (formerly called Mitosis Promoting Factor, MPF), which is responsible for the phosphorylation of spindle proteins, histones, and lamins. Phosphorylation of lamins results in their breakdown as well as the dissolution of the nuclear envelope. There are different cyclins and Cdks for each of the cell cycle checkpoints. Overarching the Cdks are the Cdk inhibitors that form an additional regulatory layer at each of the cell cycle checkpoints. The Study of the cell cycle is critical to an understanding of the regulation of abnormal proliferation as occurs in cancer cells. Two tumor suppressor genes that have been well studied are the retinoblastoma gene (Rb) and p53. Rb is active (suppressing growth) in the hypophosphorylated state and inactive in the hyperphosphorylated form. In its nonphosphorylated form, Rb serves as a brake on the cell cycle at the G1/S interface by binding to the transcription factor, E2F. Stimulation by growth factors results in phosphorylation and release of the brake; E2F is free to turn on transcription of cell cycle genes, allowing cells to traverse the G1/S interface. Mutations in Rb occur in tumors; a mutation has the same effect as inactivating Rb leading to uncontrolled cell proliferation as E2F transcribes cell cycle genes. p53 is a protective gene or molecular policeman, which prevents the replication of damaged DNA and stimulates repair. p53 acts as a transcription factor and also works through the Cdk inhibitors to arrest the cell cycle at the G1/S interface. p53 mutations are found in many human tumors.
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