Exam 2 Flashcards
What is gluconeogenesis?
making glucose from pyruvate
What is glucose?
breaking down glucose into pyruvate
What is PEPCK
regulated by Fox01 which activates it
What does Akt do in relation to Fox01?
it phosphorylates it not allowing it into the nucleus to transcribe
What does act do with glyconeogenesis
It inhibits GSK3-B which inhibits glycogen synthase which would inhibit glycogen synthase but with it inhibited more glycogen is created
What is antagonistic pleiotropy?
- genes conveying a benefit for fitness early in life will be selected even though they may be disadvantageous in later life. May contribute to the aging process.
What do the various cyclin molecules do in the cell cycle?
o Cdks (Cyclin-Dependent Kinases): Activity changes as progresses through cell cycle
o Cyclins:Regulate cdk activity through direct binding with 4 classes:
➢ G cyclins: promotes passage through Start (Cyclin D)
➢ G1/S cyclins: Bind cdks at end of G1 and commit to DNA replication (Cyclin E)
➢ S-cyclins : Initiate DNA Replication (Cyclin A)
➢ M-cyclins: Triggers entry into Mitosis (Cyclin B)
o CKIs (Cdk inhibitor proteins): Negatively regulate cell cycle
o The progression of the cell cycle occurs through a combination of: transcriptional regulation, cyclical proteolysis, and activity regulation
What occurs at the G1 phase?
• G1 phase, cell cycle initiates when cell receives an extracellular signal from “mitogens”- G1 phase Cyclin 1 CDK- phosphorylats and
What occurs at the G1/S phase?
• G1/S phase- DNA damage main driver. p53- is the gatekeeper of the genome is activated in many stressful situations, DNA damage will be sensed by proteins and p53 is phosphorylated and then accumulates in the cell.
What occurs at the Sphase?
• S phase initiates origin firing prevents pre replication- using cyclin A and cdk 2
What occurs at the M phase?
entry into M phase begins with the upregulation of cyclin B (M-cyclin) transcription, the activation of cdc25 (polo kinase, cdk1), removes inhibitory strain on cdk1, which triggers mitosis. M-cyclin binds to Cdk1 in inactive form, and then the cdk activating or inhibiting kinase removing the phosphate via a phosphatase which becomes active with a phosphorylation of cdc 25. M-cyclin comes together and becomes activated when they are dephosphorylated. Then the active-M-cdk with only one phosphate
What occurs at the metaphase to anaphase phase?
• Metaphase to Anaphase checkpoint- APC- anaphase-promoting completx, with a ubiquitin ligase- which initiates proteasomal degradation, initiates sister-chromatid separation, degradation of securing- releasing cohesions. Leads to the degradation of securing which allows the sister chromatids to actually separate.
What happens at the G2/M phase
G2/M-DNA damage inactivates cdc25- inhibited if there is DNA damage affecting the phosphatase which inhibits the earlier phosphate adding to the Cdk.
What occurs at the G0 phase?
allows cell to carry out physiological role without diverting energy to cell cycle.
What is cell senescence?
o Cells are NOT DEAD!- this isn’t apoptosis so they are irreversibly arrested but not apoptosis
o Alternative to death
o Enlargement of size of nucleus
o Distance between cells becomes greater
o Irrreversibly arrested in G0 (therefore different from quiescent cells)
o Only affects mitotic cells
What causes cells to senesce?
DNA damage, telomere shortening, and stress
What is telomere shortening?
evolved as a way of loss of coding sequence, losing telomeres instead of losing genes that code for things. predicts that repeated replication of a chromosome shortens the telomeres to the point at which no further replication can occur without affecting the coding sequences of the DNA.
➢ The repetitive, noncoding base-pair sequences at the ends of each chromosome
➢ Replication of the lagging strand template results in the loss of a short segment of the telomeres
➢ After repeated cell divisions, eventual complete loss of telomeres
➢ Telomerase: telomere elongation, protecting it.
➢ Only in germ line and stem cells: cells which require high fidelity during replication (only care about those germ cells…)
➢ Mitotic Clock Theory: predicts that old cells sense short telomeres, which, in turn, causes cell cycle arrest
➢ telomere shortening activates p53 upregulating p21 inhibit cell cycle from dividing and eventually lead to senescence
➢ Attractive model because: it is well known phenomenon that occurs with age, gametes have a way to overcome this stress (telomerase), but it is hard to decide if telomere shortening is simply a cause of aging (like grey hair) or a diriver of the aging process
How does DNA damage lead to senescence/
DNA damage via oxygen radicals, UV light, x-rays, errors in replication. Use base-excision repair removing the base, nucleotide excision repair- remove strands, recombination repair, and mismatch repair- repair the base. Try to repair and if you cant you want that cell to die or senesce
How does replicative senescence cause aging in organisms/
SASP (Senescence-Associated secretory Phenotypes)- with cellular senescence occurring over time in vitro, proliferative capacity decreased with age. Senescent cells secrete interleukins, inflammatory cytokines (IL-6), and growth factors (MPs) that can affecting the surrounding cells. Can secrete things for them to become cancerous
• Cellular Senescnce when you are young is cancer prevention regulation, but with prolonged senescence promoting aging and cancer
What is the free radical theory of aging?
o Oxidative damage caused by Free radicals drives the aging process, Denham Harman developed hypothesis in 1956 with lots of supporting data, with no direct evidence.
o Theory has evolved: “mitochondrial theory of aging”-oxidatve damage to the mitochondria itself drives the aging process
o Free radicals are Reactive Oxygen species (ROS), defined as reactive chemical species having a single unpaired electron in their outer orbit. O2-, OH-, and H2O2
o ROS is produced in peroxisomes, released by phagocytic cells, and the biggest source is mitochondria producing 95% of them
What can these radical oxygen species damage?
Biological membranes, DNA and RNA, and proteins cross linking them making them not function
how doesradical oxygen damage affect phospholipids and how do u remove it?
➢ Oxidative stress causing the double bonds to break as it is susceptible to attack by OH with liquid peroxide (lipid peroxidation) affecting people in diseases such as artherosclerosis, stroke, alzherimer’s disease
➢ Removal of lipid damage: multi-step process that includes Vitamin E, Vitamin C, Glutathione, and NAD+
How does radical oxygen damage affect DNA?
breaks the base and sugar backbone. Activated DNA repair pathways can cause senescence which can help avoid mutations by shutting down replication, but these same pathways can eventually cause aging
What is autophagy?
degradation of intracellular components in lysosomes, including damaged organelles and damaged biomolecules, components are then recycled for use in making new proteins, lipid and to synthesize new DNA
Why do we have autophagy?
alternative source of energy (during starvations. Cellular quality control (degrade damaged proteins) to turnover of cellular components and removal of damage before they interfere with normal cell function.
What are the modulators of autophagy?
o Modulators of autophagy with nutrient signaling (starvation activates autophagy) such as mTOR, Ras/PKA, Insulin activating autophagy due to starvation. Stress response (damaged biomoleculesactivate autophagy such as ER stress, hypoxia, oxidative stress, pathogen infection.
What is mTOR?
➢ mTor (mechanistic target of Rapamycin)- when nutrients are high, mTOR is activated to promote protein synthesis and inhibit autophagy through the phosphorylation of ULK1 but when mTOR is inhibited, the “brakes” are relased and autophagy will ensue. Inhibitors of this pathway are rapamycin and analogs, Torin1 PP242. When mTOr is activte inhibiting ULK complex. when reduced in all organisms they have extended life span
What proteins are involved in induction that when halted stop autophagy?
ULK-1, Atg17, and Atg13
What does rapamycin do?
rapamycin activates autophagy by inhibiting mTOR
What does sirtuin do?
o Regulate the acetylation of histones and other proteins:p53, Foxo1
What does the TOR pathway do?
Controls and regulates protein synthesis and growth in response to nutrients.
What does dietary restriction do?
with 30-40% less calories it is the o Only nongenetic method to extend life span to date
Why is it believed that calorie restriction works?
restriction will reduce the rate of metabolism thereby reducing the production of damaging free radical. After prolonged dietary restriction they have increased metabolisms such as oxygen consumption, which is not what we expected and a mix of if oxidative damage is caused by dietary restriction.
What would dietary restriction look like with genetic or pharmaceutical?
Genetic or Pharmaceutical- Longest life span curve is in the sweet dietary restriction line, if you treated with drug mimetic it would be moved to the right so same amount as normal and the same life span. Drug that inhibited bell curve so gene was regulatory of dietary restriction or deleted the gene. If there was an additive there would be an extension and would be a separate pathways with a lifespan extension and reduction because it is shifting downwards but still the same general format.
