Part 5 (final exam)The cell cycle and its control- Countless divisions of a single-celled zygote produce a cellular complex organism- Cell division doesn't stop with formation of a mature organism...continues throughout its life- 25 million cells undergo division each second in an adult human-replacing cells that have aged or died- Mothers and daughters:o Each diving cell is called a mother cell and its descendants are daughter cellso A mother cell transmits copies of its genetic information to its daughter cells, which become the next cell generationo The cell cycle starts with cell division and ends with daughter cell formation or death- the stages through which a cell passes constitute the cell cycle- Phases of the cell cycle:o 1. M phase- “mitotic” Mitosis- separation of chromosomes (nuclear division)- Only a small percent of cells in a tissue/cell culture is in mitosis at any given time- Macromolecular synthesis is relatively inactive during mitosis- 5 stages of Mitosis:o Prophaseo Metaphaseo Anaphaseo Telophase Cytokinesis- cytoplasmic division into 2 daughter cells (cell division)- Includes anaphase and telophaseo 2. Interphase- occupies bulk of the cycle: hours, days, weeks, or longer, depending on cell type and conditions Preparations for upcoming mitosis occur:- Replication of cell’s DNA- Cell grows in volume- Cell does active metabolic functions (glucose oxidation, replication, transcription, translation) Divided into:- G1 (first gap phase)o Most variable stageo Most cells that have stopped dividing (temporarily or permanently) stop before initiation of DNA synthesis in a special G1 state, called G0 Cells exit from cycle in G1 and are held in G0, where they continue to perform functions, but don’t divideo Cells must generate an internal signal to go from G0 or G1 to S - S Phase (DNA synthesis)- G2 (second gap phase)- Cell cycles in vivo (living organisms)o 3 broad categories of cells: 1. Cells with extreme structural specialization; have lost the ability to divide (nerve, muscle, RBCs)- Once differentiated, they remain in that state until they die 2. Cells that normally do not divide, but with the right stimuli, make DNA and divide- Liver cells- induced to divide if surgically remove part of the liver- Lymphocytes- divide when exposed to the right antigen 3. Cells that are normally highly mitotic; tissues subject to continual renewal by production of new cells (divide at a high rate)- Spermatogonia that become sperm- Epithelial cellso Lengths of cell cycles are variable, particularly at different stages of development <30 minutes in very rapidly dividing cleaving embryo cells- Not mammals, which cleave very slowly Several months in slowly-growing tissues, like mammalian liver Rapidly growing adult cells typically divide every 12-36 hourso Transition points Two main “transition points” in the cell cycle- 1. Initiation of DNA replication (start checkpoint)o At transition between G1 and So Checks if environment is favorable- if there is enough room- 2. Initiation of mitosis (G2/M checkpoint)o At transition between G2 and Mo Checks if all DNA is replicated and if environment is favorable Third checkpoint at anaphase, before chromosomes separate (metaphase-to-anaphase transition)- trigger anaphase and proceed to cytokinesis- Checks to make sure all chromosomes are attached to the spindle- The cell cycle control system triggers the essential process of the cycle- such as DNA replication, mitosis, and cytokinesis- The controller rotates clockwise and triggers these processes when it reaches specific checkpoints on the outer dial- Information about the cycle events and signals from the environment can cause the control system to arrest the cycle at these checkpointso A cytoplasmic factor can trigger passage through the transition points into S or M Rao & Johnson- used a virus to fuse cells in different stages of the cycle- A) Fuse G1 cells + S cells the nucleus that was originallyfrom the G1 cell enters the S phaseo S Cells have replication signal(s) that stimulate the initiation of DNA synthesis in nucleus from G1 cell- B) Fuse G2 cells + M cells the nucleus that was originally from the G2 cell undergoes premature chromosomal condensation in preparation for mitosiso M cells have replication signal(s) that stimulate mitosis in the nucleus from G2 cell- Concluded that transitions of donated nuclei (G1 S and G2 M) were induced by the presence of some stimulatoryagent in the cytoplasm of S and M cells-o Cyclin-dependent kinases and cyclins are the main cytoplasmic proteins that trigger passage through the transition points Entry into S or M is triggered by activation of a cytoplasmic factor- a two-subunit protein kinase (in the case of entry into M this has been called a maturation-promoting factor; MPF) Components of the protein kinase or MPF that controls progressionthrough the cell cycle: 1. Cyclin-dependent kinase (Cdk)- a catalytic subunit- Phosphorylates serine/threonine residues on proteins involved in mitosis or DNA synthesis, so as to tigger their activityo Nuclear proteins (histone H1)- phosphorylation mayhelp compact chromosomeso Nuclear lamins (line the nuclear envelope)- phosphorylation leads to disassembly of nuclear envelopeo Phosphorylated cytoplasmic proteins- may be needed for dynamic changes in cytoskeleton organization characterizing shift from interphase to mitosis- Cdk levels are constant throughout the cell cycle 2. Cyclin- a regulatory subunit- A family of proteins whose concentration rises and falls predictably during the cell cycle- Regulates the activity of the catalytic subunito When a cyclin is present in the cell, it binds to the Cdk, causing a change in conformation- Cyclin binding causes a flexible loop of the kinase’s polypeptide chain to move away from the active site; allows kinase to phosphorylate its protein substrates- Different cyclin genes are expressed at different stages of the cell cycle- allows for fine tuning of kinase function- The levels (concentration) of the cyclin increase and decrease. The level increases just before the checkpoints, where they will bind to Cdk to activate it- Cyclin levels regulate MPF or Cdk activityo Low cyclin MPF activity lowo High cyclin MPF higho Role of multiple cyclins and Cdk’s in the mammalian cell cycle- Interaction between various members of the Cdk gene family and the cyclin gene family
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