Cell Cycle Regulation

Cell Cycle Checkpoints Interphase consists of three phases: growth, synthesis of DNA, and preparation for mitosis (I,M,I,M,I,M,I,M) How does the cell make sure, for example, replication has been completed before moving onto G2? CHECKPOINTS – a critical control point to STOP or CONTINUE the cycle G 0 – cell cycle arrest. Not growing.

Importance of Cell Cycle Regulation Stem cells: non-specialized cells that differentiate into specialized cells via external cues Out of control cell growth = TUMORS / CANCER!

Important Checkpoints G1 checkpoint: cells will be stuck in G 0 phase unless given the go-ahead to start growing in G1. Most cells (unlike muscle and nerve cells) are in the G1 phase S/G2-phase checkpoint: makes sure all DNA is replicated before moving on and preparing for mitosis. That would be bad if a cell ended up with only a partial genome! M-phase checkpoint: makes sure all kinetochores are attached to spindle fibers before going on to anaphase (Apart). This is important because we can’t have a cell in the body that’s missing a chromosome! What if that cell needs to transcribe a gene located on it! If cells are told to STOP they are usually terminated via apoptosis (programmed cell death)

Cell Cycle Regulation The timing and rates of cell division in different parts of an animal or plant are crucial for normal growth, development, and maintenance The frequency of cell division varies with cell type Skin cells divide twice a day sometimes Many liver cells kept in G 0 phase as a reserve Muscle cells & nerve cells don’t divide once fully differentiated (always in G 0 ) We must understand molecular regulation and cues for each cell type if we are to understand and stop cancer growth

Internal & External Cues Internal and external signals provide stop-and-go signs at the checkpoints External: if there are not enough nutrients in the cell medium than the cell will not divide and visa-versa. Internal: remember, surface-area to volume ratio has to be kept small. If the cell grows to big in the G1 phase, than the cell can’t get things in and out of the cell because the volume is too it get’s the internal signal to start synthesizing it’s DNA to soon divide. There must be factors…specific things…that help identify these cues….

The ‘Stuff’ of Cell Cycle Regulation Located in the cytoplasm of the cell How do we know this? Fusion of a cell in M-phase with a cell in G1-phase will activate the non-mitotic cell to start undergoing mitosis These molecules trigger & coordinate key events in the cell cycle and they ‘decide’ whether or not it can continue. Who are these ‘bouncers’?

INTERNAL: Cyclins and CDK’s Cyclins and ‘cyclin-dependent kinases’ control the cell cycle The CDK’s are kinases, which means they are enzymes and give the cell the go-ahead to continue through cycle CDK’s not active unless bound to a cyclin molecule Different cyclin concentrations vary dramatically at different stages in the cell cycle. Each type of cyclin controls a different checkpoint. By binding to the CDK available, this cyclin/CDK pair say GO AHEAD! Active Cdks function by phosphorylating proteins

Control of Cyclin Expression Our body molecularly controls (transcription) the expression of these cyclin proteins throughout the cycle Remember, if the right cyclin isn’t available at the right time, it’s a no-go! Oftentimes In cell signaling, phosphorylation is a way to activate a protein.

Regulation overload Cyclin/CDK pairings control the cell cycle checkpoints, but lots of other proteins control the cyclin’s and CDKs! AHHH!!!! Don’t worry, you don’t have to memorize this

Mitosis-Promoting Factor (MPF) A type of cyclin that gets the cell through the M-phase checkpoint MPF also promotes disintegration of the nuclear envelope AP suggested you know this one

External Signals Growth factors: proteins released by one group of cells that stimulate other cells to divide Ex. Platelet-derived growth factor (PDGF) – produced by platelet blood cells, travel through circulatory system and bind to tyrosine kinase receptors on fibroblasts, causing a signaling cascade within the fibroblast that causes it to undergo mitosis In a living organism, platelets release PDGF in the vicinity of an injury for wound healing

P53 – cell cycle regulator Think of P53 as the judge, jury, and executioner. Once DNA is damaged in a cell, there are four fates 1. repair of that DNA  save cell 2. Apoptosis  kill that cell! You get a mutation in your p53 gene, you are definitely getting cancer 

RAS – signal transduction If you get a mutation that could lead to increased cellular signalling, you are very likely to get cancer Overstimulation of the RAS protein is a common form of cancer Point is, all cancers are different! That’s why they are so hard to treat. Your DNA can be damaged anywhere!

Cause of Cancer Cancer ALWAYS starts with DNA ANYTHING that damages the DNA is a cell can cause that cell to transform into a cancer cell This damaged cell bypasses all cellular control systems

Pathophysiology of Cancer Cancer cells have bypassed the checkpoints and cells grow uncontrollably Excessive transcription of growth factors (PDGF) Abnormalities in cell signaling Mutations in cell cycle regulators (p53, RAS) Normal cells have a lifespan of divisions but come cancer cells are immortal. One cell line from 1951 is still reproducing in culture!

Pathophysiology of Cancer All it takes is ONE damaged cell Normally the immune system would catch it, but if not, it can divide uncontrollably Benign tumors are unable to metastasize (invade neighboring tissue) and are not considered cancer Malignant tumors are able to metastasize

BRCA Genes People who carry the mutated forms of these genes are more likely to develop breast cancer, ovarian cancer, and prostate cancer in the case of men These genes are, therefore, biomarkers for cancer predisposition HOWEVER, only 10% of all breast cancers are caused by this mutation

Embryonic Stem Cells What makes these cells different from other cells in our body? Most cells in our body are fully and differentiated specialized. ESC’s can be either: Totipotent: can become any type of cell, tissue, organ, or entire organism. Pluripotent: can become many types of cells, tissues, or organs Undifferentiated: has the ability to follow any differentiation pathway. Unspecialized: can give rise to specialized cell types

Stem Cells Every cell in our body came from one of three cell lineages that originated in the blastocyst stage of development Ectoderm Mesoderm Endoderm Even in our bodies now, we have cells that can differentiate into different types of cells

Medical Uses of Stem Cells Repair of brain and spinal tissues. Treatment of diseases such as leukemia, str oke, Alzheimer’s, Parkinson’s, diabetes, cystic fibrosis. Therapeutic cloning of human cells, tissues, and certain organs (e.g., bone, cartilage, muscle). Reprogramming of diseased cells. Testing of new drugs. Storage of umbilical cord stem cells. One day, doctors treating a cancer patient with chemotherapy may be able to replace his or her damaged blood or marrow cells with new ones grown from ES cells.

Ethical Considerations Is it ethical to use embryonic stem cells? Different external cues (growth factors)

WHAAATTT!? Possible alternatives