Cell Bio Apop/Cell Cycle (6)

an increase in cell size; also used to describe tissues and organs that have enlarged (NOT an altered proliferative state)

• Regeneration
• Metaplasia
• Hyperplasia
• Dysplasia
• • altered growth states in tissues can reverse back to normal or at least stop progressing if the stimulus that provoked the proliferation is removed

a one-for-one replacement of cells; type of reversible proliferation state

• increase in number of fully differentiated/functions cells in a tissue (more than normal; in response to some kind of stimulus, eg. injury)
• • disease examples: Restenosis [following vascular surgery], Grave's disease

• • if endothelial cells don’t regenerate quickly enough after a balloon angioplasty, then smooth muscle cells can become hyperplastic
• • this is problematic b/c excessive smooth muscle cells causes re-blockage (restenosis) of the blood vessel that was JUST opened

• • a form of hyperthyroidism
• • hyperplasia occurs: too many thyroid cells that are all fully differentiated
• • with the increase of cells comes an increase of thyroid hormone production --> leads to increased metabolic rate, weight loss, bulging eyes, and strabismus

• overproduction of thyroid hormones --> increased metabolic rate, increased ocular pressure
• • Grave's Disease = most common form of hyperthyroidism

adaptive substitution of one cell type by another cell type; ALWAYS pathogenic

• 1) Lung – in smokers, heat and smoke cause normal cells to be replaced by other, more protective cells
• 2) Cervix: Chronic Inflammatory Pelvic Disease
• • normal columnar is replaced by a stratified squamous epithelium
• • more protective squamous epithelium lacks cilia and can't move mucus along well creating a rich environment for bacterial/viral replication

• changes in mitotic rate of cells, loss of positional control, and loss in the uniformity of cell shape (pleiotropy)
• • often a precursor to cancer
• • seen in the exocervix where it is often a precursor to CERVICAL CANCER (reason for pap smears)

malignant neoplasia or malignant tumor; cell has to lose both proliferation controls and positional controls to be cancerous

• proliferation continues even in the absence of an external stimulus (NOT CANCER)
• • NON-reversible proliferation state

• loss of proliferation control only; "benign" tumors, like fibroids
• • when there the loss of proliferation control, but NO loss of position control; means that a tumor will result but can't spread

• clinical correlate: BENIGN NEOPLASIA
• • these are benign tumors that grow in the uterus
• • positional control is retained.
• • tumors cause severe pain, bleeding and infertility

• loss of BOTH proliferation and positional controls
• • (eg. metastatic tumors, "cancer")

clinical correlate: MALIGNANT NEOPLASIA

Centromeres are attached to microTUBULES and cytokinesis is orchestrated by microFILAMENTS

• proliferation rate
• • partly b/c information in the extracellular matrix helps regulate cell proliferation
• • eg. epithelial cells in intestinal crypt

• G1prepares cell for replicating DNA; cell is busy doubling its contents in preparation for an eventual cell division
• S
• G2
• M

prepares cell for replicating DNA; cell is busy doubling its contents in preparation for an eventual cell division

• checkpoint between G1 and S where the cell has the option to exit the cell cycle & enter a quiescent state called G0
• • cells go into G0 based on their nutritional state, positional information, density/contact/ shape/stretch information, and matrix information

• normally inactive (hypophosphorylated) and complexed w/ TFs needed for cell proliferation
• • this prevents them from binding to DNA
• • during correct passage through the R checkpoint, cyclin D/cdk4-6 and cyclin E/cdk2 complexes phosphorylate Rb, changing its conformation and releasing the TFs

• • active: UNphosphorylated, complexed with TFs
• • inactive: phosphorylated, NOT complexed with TFs
• • in tumor cells, the Rb protein is missing or defective.

• 1) external signals (growth factors) stimulate synthesis of cyclins D & E
• • cyclin D partners w/ cdk4 or 6
• • cyclin E partners w/ cdk2
• 2) when enough cyclin D/cdk4-6 and cyclin E/cdk2 are activated, they phosphorylate Rb protein
• 3) the TFs released from Rb bind to DNA and activate transcription that encodes proteins which push cells through the R-point --> into S-phase
• • once DNA synthesis starts a protease is activated & destroys cyclins D & E inactivating kinase complexes

DNA replication

prepares cell for segregation/division of genome and cytoplasm

chromosome segregation (mitosis) and separation of daughter cells (cytokinesis)

• • monitor the health of the nuclear genome (i.e., DNA damage, completeness of DNA replication, alignment of chromosomes
• • monitor availability of key nutrients and cytokines in the environment

CANCER cells; they plough through & if they start making DNA and don't have enough material they'll happily die

• regulates mitosis; made up of two cyclins: cyclin B & cdk1
• • the key substrates for cyclin B-cdk1 are laminas and histones
• • think back to lecture 1: at the start of mitosis, laminas are phosphorylated, causing nuc. membrane disassembly, while the histones are phosphorylated, cause chromosome CONdensation

• cell proliferation
• • seen in thymus, spleen, small intestine, epidermis, & ovarian follicles

• •'accidental' cell death
• •triggered by sustained ischemia, physical or chemical trauma (eg. ionic shock)
• •cells and organelles swell, organelles damaged, •chromatin randomly degraded
• •cells LYSE
• •INFLAMMATORY RESPONSE OCCURS

• •programmed cell death triggered by specific signals that activate specific genes
• •cells shrink, organelles intact, & chromatin is degraded systematically
• •membrane blebs (chunks of cell) can be phagocytosed by neighboring cells
• •NO INFLAMMATORY RESPONSE

• clinical correlate: APOPTOSIS
• •autosomal dominant
• •results in uncontrolled APOPTOSIS of kidney cells.
• •get kidney tissue full of cysts b/c cells that have died from apoptosis leave spaces that become filled with fluid --> creating cysts.

• 1) Induction: intrinsic or extrinsic
• 2) Modulation
• 3) Execution: caspases --> endonucleases
• (I'm Meredith Elman)

• intrinsic and extrinsic pathway inducers:
• • intrinsic = growth factor withdrawal, survival factor withdrawal, glucocorticoids
• • extrinsic = TNF-alpha, FasL

viral infection, heat shock, toxins, tumor suppressors, oxidants/free radicals

UV/gamma radiation, chemotherapeutic drugs

• •growth factor withdrawal
• •survival factor withdrawal
• •glucocorticoids
• -intrinsic often called mitochondrial pathway

• • upon mild ischemia, removal of nutrients, there is a withdrawal of growth factors (& the like)
• • when apoptosis signal is received, pro-apoptotic Bcl-2 proteins (eg. BAD) are DEphosphorylated
• • they bind to others on the outer mitochondrial membrane
• • this results in loss of mitochondria membrane channel control and cytochrome C is released
• • helps cleave caspase 9 --> begins caspase amplification

• •TNF-alpha
• •FasL (Fas ligand)

• • via receptor mediated apoptosis
• • 2 death receptors may be expressed on a cell's membrane: TNF-alpha & FasL (fas ligand system, or FasL receptor)
• -almost all cells have TNF-alpha receptors in their membrane
• • a cell presenting a ligand will live
• • cells with receptors will DIE
• • once bound the receptor's death domain is activated and initiates caspase cascade

both pro- and anti-apoptotic family of proteins

• clinical correlate: apoptosis modulation, BcL proteins
• •individual produces LOTS of pro-life Bcl proteins (eg. Bcl-2, Bcl-X1) but low levels apoptosis-inducing Bcl proteins (eg. BAD)
• •results in excessive overgrowth of cells

• • intrinsic: Bcl protein dephosphorylation, complexing, and openings of mitrochondrial membrane channels to release cytochrome C
• • extrinsic: binding of a TNF-alpha or FasL ligand to their respective receptors

• 1) intrinsic pathway is activated by: growth factor/survival factor withdrawal, glucocorticoids, viruses, DNA damage-causing events, toxins, oxidized compounds (free radicals), and ischemia
• • extrinsic pathway is activated by TNF-alpha or Fas ligand binding to their receptors on the cell surface
• 2) intrinsic, NOT the extrinsic pathway, can be modulated by the Bcl family proteins
• 3) similarity: both pathways result in massive amounts of caspase-3 activity --> the chief executioner of cells undergoing apoptosis

cleaves cytoskeletal fibers and activates specific endonuclease that makes the ladder; common enzyme in apoptosis cascade

• • via the EXTRINSIC pathway
• • all T-cells have Fas RECEPTORS on their surface
• • blood vessels lining immune privileged sites constitutively express Fas-LIGAND on their endothelial cells
• • when T-cells enter blood vessels lining privileged sites, Fas receptor on T-cells interacts with Fas-Ligand on endothelial cells
• • T cells are induced to undergo apoptosis

HYPOthyroidism: apoptosis of thyroid cells leads to compromised thyroid function

• • Syndactyly + polydactyly
• • cancers expansion
• • cachexia (“wasting”) seen in some late-stage cancer patients
• • Polycystic Kidney Disease
• • Hashimoto’s (autoimmune form of hypothyroidism)

• • clinical correlate: anti-apoptosis drugs
• • inhibitors of apoptosis (IAPs) exist in humans; neuronal IAP can protect stroke victims from excessive loss of neurons if given in time