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Cell division, cell growth, cell Cycle
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Interphase and meiosis I
Centrosomes (with centriole pairs) Sister chromatids Chiasmata Spindle Tetrad Nuclear envelope Chromatin Centromere (with kinetochore) Microtubule attached to kinetochore Tertads line up Metaphase plate Homologous chromosomes separate Sister chromatids remain attached Pairs of homologous chromosomes split up Chromosomes duplicate Homologous chromosomes (red and blue) pair and exchange segments; 2n = 6 in this example INTERPHASE MEIOSIS I: Separates homologous chromosomes PROPHASE I METAPHASE I ANAPHASE I Figure 13.8 2. cross over 1. Synapsis (聯會) (synaptonemal complex)
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MEIOSIS II: Separates sister chromatids
Telophase I, cytokinesis, and meiosis II TELOPHASE I AND CYTOKINESIS PROPHASE II METAPHASE II ANAPHASE II TELOPHASE II AND MEIOSIS II: Separates sister chromatids Cleavage furrow Sister chromatids separate Haploid daughter cells forming During another round of cell division, the sister chromatids finally separate; four haploid daughter cells result, containing single chromosomes Two haploid cells form; chromosomes are still double Figure 13.8
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(before chromosome replication)
A comparison of mitosis and meiosis MITOSIS MEIOSIS Parent cell (before chromosome replication) Chiasma (site of crossing over) MEIOSIS I Prophase I Prophase Chromosome replication Chromosome replication Tetrad formed by synapsis of homologous chromosomes Duplicated chromosome (two sister chromatids) 2n = 6 Chromosomes positioned at the metaphase plate Tetrads positioned at the metaphase plate Metaphase I Metaphase Anaphase Telophase Sister chromatids separate during anaphase Homologues separate during anaphase I; sister chromatids remain together Anaphase I Telophase I Haploid n = 3 Daughter cells of meiosis I 2n 2n Daughter cells of mitosis MEIOSIS II n n n n Daughter cells of meiosis II Sister chromatids separate during anaphase II
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Cell cycle: --- the life of a cell from the time it is first formed from a dividing parent cell until its own division into two cells. Smallest unit of life all living things must reproduce Cells replicate for growth, replacement, and repair Cell division functions in reproduction, growth, and renewal. 200 µm 20 µm
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Cell Cycle The Cell’s Time Clock
Cell division requires Mitosis & Cytokinesis Phases of a dividing cell’s life interphase cell grows replicates chromosomes produces new organelles & biomolecules mitotic phase cell separates & divides chromosomes mitosis cell divides cytoplasm & organelles cytokinesis Cytokinesis
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Cell cycle Cell has a “life cycle”
cell is formed from a mitotic division cell grows & matures to divide again cell grows & matures to never divide again G1, S, G2, M liver cells G0 epithelial cells, blood cells, stem cells brain nerve cells
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Interphase Cell performs normal function Three subphases:
G1: cell duplicates most organelles S: quantity of DNA in the cell is doubled as chromosomes are replicated. Each chromosome has a pair of sister chromatids connected by a centromere that contains a kinetochore G2: chemical components stockpiled Nucleolus present Interphase
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Mitosis Nuclear division without a reduction in chromosome number
Each new cell (daughter cell) will have the same quantity of DNA as the parental cell Why is this important? Mitotic events can be categorized into discrete stages based on what is happening to structure of the cell Stage include: Prophase Prometaphase Metaphase Anaphase Telophase
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Prophase (Including Prometaphase)
Three things visibly occur Chromosomes condense (shorten) Centrosomes migrate to the poles while producing spindle fibers Nuclear membrane fragments
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Metaphase Metaphase Plate Meta Chromosomes are moved by growing spindle fibers to the equator of the cell (metaphase plate) Centrosomes are at the poles, nuclear membrane is gone
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Anaphase Ana Centromere splits into two
Spindle fibers shorten from kinetochore end separating sister chromatids Activated kinetochores “pull” chromatids along the spindle fibers and toward the poles
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Telophase Telo Nuclear membrane reforms around each region of chromosomes Nucleolus reforms Cytokinesis (division of the cytoplasm) may occur
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Cytokinesis May Vary Between Major Taxonomic Groups
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Cytokinesis divides the cytoplasm
* Cleavage furrow * No cleavage furrow Cleavage furrow Contractile ring of microfilaments Daughter cells 100 µm (a) Cleavage of an animal cell (SEM) Daughter cells 1 µm Vesicles forming cell plate Wall of patent cell Cell plate New cell wall (b) Cell plate formation in a plant cell (SEM) Actin + Myosin
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Regulation of Cell Division
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Coordination of cell division
A multicellular organism needs to coordinate cell division across different tissues & organs critical for normal growth, development & maintenance coordinate timing of cell division coordinate rates of cell division not all cells can have the same cell cycle
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Activation of cell division
How do cells know when to divide? cell communication signals chemical signals in cytoplasm give cue signals usually mean proteins activators inhibitors experimental evidence: Can you explain this?
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Frequency of cell division
Frequency of cell division varies by cell type embryo cell cycle < 20 minute skin cells divide frequently throughout life 12-24 hours cycle liver cells retain ability to divide, but keep it in reserve divide once every year or two mature nerve cells & muscle cells do not divide at all after maturity permanently in G0 G2 S G1 M metaphase prophase anaphase telophase interphase (G1, S, G2 phases) mitosis (M) cytokinesis (C) C
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Overview of Cell Cycle Control
There’s no turning back, now! Two irreversible points in cell cycle replication of genetic material separation of sister chromatids Checkpoints process is assessed & possibly halted centromere sister chromatids single-stranded chromosomes double-stranded
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Cell Cycle Regulation Cell cycle events are triggered by the cell-cycle control system; a set of molecules found in the cytoplasm affected by internal and external controls Checkpoints in G1, G2, and M phases of the cycle G1 checkpoint is most critical. May throw cells out of cyclic phase into G0, never to divide again
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Other Internal and External Factors
M checkpoint does not proceed until signal is received that all kinetochores are attached to spindle microtubules External Growth factors: cycle will not proceed if requirements are not met Social signals Density-dependent inhibition: under crowded conditions chemical requirements are insufficient to allow cell growth Anchorage dependence: some cells must be attached to a substrate in order to replicate DNA damage inhibits growth
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External signals: ex. Growth factors
~ Cells fail to divide if an essential nutrient is left out of the culture medium. ~ GFs trigger a signal transduction pathway that allows the cells to pass the G1 checkpoint and divide. PDGF PDGF receptor cell Signal transduction Cell division
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External signals Growth factors coordination between cells
protein signals released by body cells that stimulate other cells to divide density-dependent inhibition crowded cells stop dividing each cell binds a bit of growth factor not enough activator left to trigger division in any one cell anchorage dependence to divide cells must be attached to a substrate “touch sensor” receptors
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External signals: physical factor
Density-dependent inhibition of cell division ~ Crowded cells stop dividing Cells anchor to dish surface and divide (anchorage dependence). When cells have formed a complete single layer, they stop dividing (density-dependent inhibition). If some cells are scraped away, the remaining cells divide to fill the gap and then stop (density-dependent inhibition). 25 µm single layer
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Most animal cells exhibit anchorage dependence
In which they must be attached to a substratum to divide Anchorage dependence * Cancer cells: ~ Exhibit neither density- dependent inhibition nor anchorage dependence Normal cell ~ single layer Cancer cells do not exhibit anchorage dependence or density-dependent inhibition. 25 µm 25 µm
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Growth factor signals growth factor cell division cell surface
nuclear pore nuclear membrane P P cell division cell surface receptor Cdk protein kinase cascade P E2F P chromosome Rb P E2F cytoplasm Rb nucleus
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Internal signal of a Growth Factor
Platelet Derived Growth Factor (PDGF) made by platelets in blood clots binding of PDGF to cell receptors stimulates cell division in fibroblast (connective tissue) heal wounds Don’t forget to mention erythropoietin! (EPO) Erythropoietin (EPO): A hormone produced by the kidney that promotes the formation of red blood cells in the bone marrow. EPO is a glycoprotein (a protein with a sugar attached to it). The kidney cells that make EPO are specialized and are sensitive to low oxygen levels in the blood. These cells release EPO when the oxygen level is low in the kidney. EPO then stimulates the bone marrow to produce more red cells and thereby increase the oxygen-carrying capacity of the blood. EPO is the prime regulator of red blood cell production. Its major functions are to promote the differentiation and development of red blood cells and to initiate the production of hemoglobin, the molecule within red cells that transports oxygen. EPO has been much misused as a performance-enhancing drug (“blood doping”) in endurance athletes including some cyclists (in the Tour de France), long-distance runners, speed skaters, and Nordic (cross-country) skiers. When misused in such situations, EPO is thought to be especially dangerous (perhaps because dehydration can further increase the viscosity of the blood, increasing the risk for heart attacks and strokes. EPO has been banned by the Tour de France, the Olympics, and other sports organizations.
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The sequential events of the cell cycle are directed by a distinct cell cycle control system, a cyclically operating set of molecules in the cell that both triggers and coordinates key events in the cell cycle. Control system G2 checkpoint M checkpoint G1 checkpoint G1 S G2 M ~ similar to a clock The cell cycle is regulated at certain checkpoints by both internal and external controls.
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Checkpoint control system
Checkpoints cell cycle controlled by STOP & GO chemical signals at critical points signals indicate if key cellular processes have been completed correctly
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Checkpoint control system
3 major checkpoints: G1/S can DNA synthesis begin? G2/M has DNA synthesis been completed correctly? commitment to mitosis spindle checkpoint are all chromosomes attached to spindle? can sister chromatids separate correctly?
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Spindle checkpoint G2 / M checkpoint M cytokinesis C G2 mitosis G1 S
Chromosomes attached at metaphase plate Replication completed DNA integrity Inactive Active Active Inactive Cdk / G2 cyclin (MPF) M APC cytokinesis C G2 mitosis G1 S Cdk / G1 cyclin Inactive MPF = Mitosis Promoting Factor APC = Anaphase Promoting Complex Active G1 / S checkpoint Growth factors Nutritional state of cell Size of cell
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G1/S checkpoint G1/S checkpoint is most critical
primary decision point “restriction point” if cell receives “GO” signal, it divides internal signals: cell growth (size), cell nutrition external signals: “growth factors” if cell does not receive signal, it exits cycle & switches to G0 phase non-dividing, working state
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G0 phase G0 phase non-dividing, differentiated state
most human cells in G0 phase liver cells in G0, but can be “called back” to cell cycle by external cues nerve & muscle cells highly specialized; arrested in G0 & can never divide
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Cell Cycle Checkpoints
If cell size inadequate G1 or G2 arrest If nutrient supply inadequate G1 arrest If an essential external stimulus is lacking G1 arrest (at R) If the DNA is not replicated S arrest If DNA damage is detected If the spindle formation is improper, chromosome misalignment M-phase arrest R
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“Go-ahead” signals Protein signals that promote cell growth & division
internal signals “promoting factors” external signals “growth factors” Primary mechanism of control phosphorylation kinase enzymes either activates or inactivates cell signals We still don’t fully understanding the regulation of the cell cycle. We only have “snapshots” of what happens in specific cases.
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Cell cycle signals Cell cycle controls cyclins Cdk’s
inactivated Cdk Cell cycle controls cyclins regulatory proteins levels cycle in the cell Cdk’s cyclin-dependent kinases phosphorylates cellular proteins activates or inactivates proteins Cdk-cyclin complex triggers passage through different stages of cell cycle activated Cdk
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Types of Cyclins and Cdks
There are many types of cyclins, but the 4 main ones are: Cyclin D (G1 cyclin) Cyclin E (S-phase cyclin) Cyclin A (S-phase and mitotic cyclin) Cyclin B (mitotic cyclin) These are the 3 main cdks Cdk4 (G1 Cdk) Cdk2 (S-phase Cdk) Cdk1 (mitotic Cdk) The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF) a.k.a maturation promoting factor
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Rise and fall of cyclins
Cyclin Concentration Mitosis
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Cdks and cyclins Cyclin-dependent kinases (Cdks) are enzymes that are present in the cell cytoplasm at all times. However, they are inactive unless they are bound by a specific partner-protein called a cyclin to form a Cdk-cyclin complex The amount of cyclins in the cell changes – because they get degraded A Cdk-cyclin complex will push the cell cycle forward.
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Figure 19-35 Phosphorylation and Dephosphorylation in the Activation of a Cdk-Cyclin Complex
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MPF: M-phase Promoting Factor
MPF is composed of two key subunits: Cdc2 and Cyclin B. Cdc2 is the protein that encoded by genes which are required for passage through START as well as for entry into mitosis. Cyclin B is a regulatory subunit required for catalytic activity of the Cdc2 protein kinase.
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What does MPF do? The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF)
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MPF activity is dependent upon Cyclin B
The cyclins were identified as proteins that accumulate throughout interphase and are rapidly degraded toward the end of mitosis. It is suggested that they might function to induce mitosis, with their periodic accumulation and destruction controlling entry and exit from M phase.
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MPF activity is dependent upon Cyclin B
Accumulation and degradation of cyclins
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Figure 19-34 Fluctuating Levels of Mitotic Cyclin and MPF During the Cell Cycle
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MPF regulation Cdc2 forms complexes with cyclin B during S and G2.
Cdc2 is then phosphorylated on threonine-161, which is required for Cdc2 activity, as well as on tyrosine-15 (and threonine-14 in vertebrate cells), which inhibits Cdc2 activity. Dephosphorylation of Thr14 and Tyr15 activates MPF at the G2 to M transition. MPF activity is then terminated toward the end of mitosis by proteolytic degradation of cyclin B.
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MPF regulation Demonstration of regulation of MPF
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Figure 19-40 A General Model for Cell Cycle Regulation
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1970s-’80s | 2001 Cyclins & Cdks Interaction of Cdk’s & different cyclins triggers the stages of the cell cycle There are multiple cyclins, each with a specific role. Cyclins are unstable. Some are triggered for destruction by phosphorylation. Others are inherently unstable and are synthesized discontinuously during the cell cycle. Oscillations in the activities of cyclin-dependent kinases (CDKs) dictate orderly progression through the cell division cycle. In the simplest case of yeast, a progressive rise in the activity of a single cyclin-CDK complex can initiate DNA synthesis and then mitosis, and the subsequent fall in CDK activity resets the system for the next cell cycle. In most organisms, however, the cell cycle machinery relies on multiple cyclin-CDKs, whose individual but coordinated activities are each thought to be responsible for just a subset of cell cycle events. Leland H. Hartwell checkpoints Tim Hunt Cdks Sir Paul Nurse cyclins
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external signals is density-dependent inhibition, in which crowded cells stop dividing but lost of contact inhibition and outgrowth in cancer cells
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Tumors Mass of abnormal cells Benign tumor Malignant tumors
abnormal cells remain at original site as a lump p53 has halted cell divisions most do not cause serious problems & can be removed by surgery Malignant tumors cells leave original site lose attachment to nearby cells carried by blood & lymph system to other tissues start more tumors = metastasis impair functions of organs throughout body
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Tumors Benign - A spontaneous growth of tissue which forms an abnormal mass is called a tumor. A tumor that is noninvasive and noncancerous is referred to as a benign tumor. Malignant - A tumor that invades neighboring cells and is cancerous is referred to as a malignant tumor. Matastasis – Cancer that has spread to other tissues.
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Development of Cancer Cancer develops only after a cell experiences ~6 key mutations (“hits”) unlimited growth turn on growth promoter genes ignore checkpoints turn off tumor suppressor genes escape apoptosis turn off suicide genes immortality = unlimited divisions turn on chromosome maintenance genes promotes blood vessel growth turn on blood vessel growth genes overcome anchor & density dependence turn off touch censor gene It’s like an out of control car!
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Cancer & Cell Growth Cancer is essentially a failure of cell division control unrestrained, uncontrolled cell growth What control is lost? checkpoint stops gene p53 plays a key role in G1 checkpoint p53 protein halts cell division if it detects damaged DNA stimulates repair enzymes to fix DNA forces cell into G0 resting stage keeps cell in G1 arrest causes apoptosis of damaged cell ALL cancers have to shut down p53 activity p53 is the Cell Cycle Enforcer p53 discovered at Stony Brook by Dr. Arnold Levine
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p53 — master regulator gene
NORMAL p53 p53 allows cells with repaired DNA to divide. p53 protein DNA repair enzyme p53 protein Step 1 Step 2 Step 3 DNA damage is caused by heat, radiation, or chemicals. Cell division stops, and p53 triggers enzymes to repair damaged region. p53 triggers the destruction of cells damaged beyond repair. ABNORMAL p53 abnormal p53 protein cancer cell Step 1 Step 2 DNA damage is caused by heat, radiation, or chemicals. The p53 protein fails to stop cell division and repair DNA. Cell divides without repair to damaged DNA. Step 3 Damaged cells continue to divide. If other damage accumulates, the cell can turn cancerous.
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Growth Factors and Cancer
Growth factors influence cell cycle proto-oncogenes normal genes that become oncogenes (cancer-causing) when mutated stimulates cell growth if switched on can cause cancer example: RAS (activates cyclins) tumor-suppressor genes inhibits cell division if switched off can cause cancer example: p53
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What causes these “hits”?
Mutations in cells can be triggered by UV radiation chemical exposure radiation exposure heat cigarette smoke pollution age genetics
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How we naturally fight cancer cells
Tumor suppressor genes like p53 Can arrest the cell cycle Can launch the apoptotic pathway, causing the rogue cells to lyse A mutation in the p53 gene can lead to cancer Immune cells (WBCs) such as NK cells can attack and lyse tumor cells Some immune cells can signal the rogue cells to launch the apoptotic pathways
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Traditional treatments for cancers
Treatments target rapidly dividing cells high-energy radiation kills rapidly dividing cells chemotherapy stop DNA replication stop mitosis & cytokinesis stop blood vessel growth
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New “miracle drugs” Drugs targeting proteins (enzymes) found only in tumor cells Gleevec treatment for adult leukemia (CML) & stomach cancer (GIST) 1st successful targeted drug GIST = gastrointestinal stromal tumors, which affect as many as 5,000 people in the United States CML = chronic myelogenous leukemia, adult leukemia
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Any Questions??
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Signal Transduction Pathways
What are they? Signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another. A large number of proteins, enzymes and other molecules participate in a "signal cascade“ What is the end result? Either the activation or inhibition of a certain enzyme in the cytoplasm Either the expression or suppression of a particular gene
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Just a few examples of Signal Transduction Pathways
Cell Division signals Apoptotic signals Insulin pathways
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Apoptotic Pathways
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Insulin Signaling Pathway
The binding of insulin to its receptor on a cell starts a cascade of cellular events which finally leads to the uptake of glucose and the lowering of blood glucose levels.
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“Go-ahead” signals Protein signals that promote cell growth & division
internal signals “promoting factors” external signals “growth factors” Primary mechanism of control phosphorylation kinase enzymes either activates or inactivates cell signals We still don’t fully understanding the regulation of the cell cycle. We only have “snapshots” of what happens in specific cases.
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