-
CELL CYCLE
M - MITOSIS
G0 - NONDIVIDING
G1 - GROWTH, CYCLIN D, Cdks 4 & 6,
S - DNA REPLICATION, CYCLIN E
CYCLIN A, Cdk 2
G2 - PREP FOR CELL DIVISION, CYCLIN B, Cdk 1
-
HOW DO CYCLINS AND Cdks STIM DNA SYNTHESIS
PROGRESSION THROUGH CELL CYCLE REQUIRES CYCLIN PROTEINS, OF WHICH THERE ARE AT LEAST 20 AND CLASSIFIED INTO A,B,D, OR E
UNDERGO SEQUENTIAL BINDING TO A GROUP OF CYCLIN DEPENDENT KINASES (CDks) THROUGHOUT CELL CYCLE FORMING SPECIFIC CYCLIN-Cdk COMPLEXES
CYCLIN-Cdk COMPLEXES PHOS A DNA BIND PROTEIN CALLED RETINOBLASTOMA GENE PRODUCT (pRb)
PHOSED pRb RELEASES TRANSCRIPTION FACTOR (eg E2F
E2F STIMS TRANSCRIPTION OF GENES ENCODING ENZYMES NEEDED FOR DNA SYNTH
-
HOW DO GROWTH FACTORS ACTIVATE PHOS CASCADES
BIND TO CELL SURFACE RECEPTORS
STIM TYROSINE PHOSPHORYLATION AND ACTIVATING CELLULAR PHOS CASCADE
-
WHAT IS ONGOGENE, HOW IS IT GENERATED, AND WHAT IS PROTO-ONCOGENE
PROTO-ONCOGENES ARE GENES WHOSE PRODUCTS FUNCTION AS REGULATORS OF NORMAL CELL PROLIFERATION OR SURVIVAL
MUTATIONS IN PROTO-ONCOs GIVE RISE TO ONCOGENES WHICH EXHIBIT INAPPROPRIATE ACTIVITIES
PROTO-ONCOs CODE FOR WIDE VARIETY OF PROTEINS SUCH AS GROWTH FACTORS, GF RECEPTORS, HORMONE RECEPTORS, CELL SIGNALING MOLECULES, TRANSCRIPTION FACTORS, AND CELL CYCLE REGULATORS
-
CLASSES OF PROTO-ONCOGENES
GROWTH FACTORS (Sis)
GROWTH FACTOR RECEPTORS (Erb-B2)
HORMONE RECEPTORS (RARa)
CELLULAR SIGNALING MOLECULES (Abl & Ras)
TRANSCRIPTION FACTORS (Myc)
CELL CYCLE REGULATORS (CYCLIN D, Cdk 4
-
LIST PROTO-ONCO, ACTIVATION MECHANISM, AND DISEASE FOR GROWTH FACTOR
PLATELET-DERIVED GROWTH FACTOR
Sis
OVER EXPRESSION
-
LIST PROTO-ONCO, ACTIVATION MECHANISM, AND DISEASE FOR GROWTH FACTOR RECEPTORS
EPIDERMAL GROWTH FACTOR RECEPTOR
Erb-B2
AMPLIFICATION
MULTIPLE CANCERS
-
LIST PROTO-ONCO, ACTIVATION MECHANISM, AND DISEASE FOR HORMONE RECEPTORS
RETINOID RECEPTOR
RARa
TRANSLOCATION
ACUTE PROMYELOCYTIC LEUKEMIA (APL)
-
LIST PROTO-ONCO, ACTIVATION MECHANISM, AND DISEASE FOR CELLULAR SIGNALING MOLECULES
TYROSINE KINASES, Abl, TRANSLOCATION, CHRONIC MYELOID LEUKEMIA (CML) /
GTP BINDING PROTEINS, Ras, POINT MUTATION, MULTIPLE CANCERS
-
LIST PROTO-ONCO, ACTIVATION MECHANISM, AND DISEASE FOR TRANSCRIPTION FACTORS
...
Myc
TRANSLOCATION LEADING TO BURKITT LYMPHOMA
AMPLIFICAITON LEADING TO NEUROBLASTOMA
-
LIST PROTO-ONCO, ACTIVATION MECHANISM, AND DISEASE FOR CELL CYCLE REGULATORS
...
CYCLIN D - TRANSLOCATION LEADING TO LYMPHOMA. AMPLIFICATION LEADING TO BREAST & LIVER CANCERS
Cdk 4 - AMPLIFICATION LEADING TO GLIOBLASTOMA. POINT MUTATION LEADING TO MELANOMA
-
HOW IS MUTATION OF Ras ONCOGENIC
SIGNALING MOLECULE WHICH BINDS GTP
NORMALLY REGULATED/INACTIVATED BY HYDROLYZING GTP TO GDP
ACTIVE FORM STIMS PHOS OF SERIES OF CYTO AND NUC PROTEINS LEADING TO CELL PROLIFERATION
MUTATION CAUSES PROLIFERATION EVEN IN ABSENSE OF GROWTH FACTORS (DESTRUCTION OF GTPase PRESENT IN Ras)
MULTIPLE CANCERS SUCH AS COLON, LUNG, PANCREASE, THYROID AS WELL AS LEUKEMIAS
-
HOW IS TRUNCATED EGF RECEPTOR ONCOGENIC
ErbB ONCOGENE IN AVIAN LEUKEMIA VIRUS WHICH CODES FOR TRUNCATED VERSION OF EGF RECEPTOR
LOSS OF EXTRACELLULAR LIGAN BINDING DOMAIN LEADS TO PERMINANT ACTIVATION IN THE ABSENCE OF EGF GROWTH FACTOR
-
HOW ACTIVATING MUTATIONS OCCUR IN RETROVIRAL ONCOGENES
ONCOGENE CARRIED WITHIN VIRAL GENOME
VIRUS INSERTS NEXT TO CELLULAR PROTO-ONCOGENE LEADING TO UP OR DOWN REGULATION OF EXPRESSION
eg TRUNCATED EGF RECEPTOR
-
MECHANISM OF ACTION OF PRODUCTS OF TUMOR SUPPRESSOR GENES pRb AND p53
RETINOBLASTOMA (pRb) BINDS EF2, KEEPING IT FROM STIMULATING TRANSCRIPTION OF GENES ENCODING ENZYMES NEEDED FOR DNA SYNTH
p53 IS A TRANSCRIPTION FACTOR THAT CAUSES PRODUCTION OF PROTEINS THAT INHIBIT CELL CYCLE, STIM DNA REPAIR, AND CAUSE APOPTOSIS
UPON DNA DAMAGE, p53 ACTIVATES p21 WHICH INHIBITS Cdks LEADING TO INHIBITION OF CELL CYCLE, INCREASED DNA REPAIR ENZYMES AND PROTEINS THAT PROMOTE APOPTOSIS
CHEMO USING DNA DAMAGING AGENTS WORK BETTER IF p53 IS PRESENT
-
WILM'S TUMOR
TRANSCRIPTION FACTOR FROM TUMOR SUPPRESSING GENE
WT-1 INHIBITS SYNTH OF GROWTH FACTOR OR GROWTH FACTOR RECEPTOR IS MUTATED
-
ATAXIA TELANGIECTASIA
PRODUCTS OF TUMOR SUPPRESSING GENES INVOLVED IN DNA REPAIR
TUMOR SUPPRESSING GENE ATM IS DEFICIENT, THUS p53 NOT STIMULATED TO REPAIR DNA DAMAGE
-
INKs
INHIBITORS OF Cdks MADE FROM TUMOR SUPPRESSING GENES
MANY CANCERS, INCLUDING MELANOMA, LUNG, AND PANC, INKs (eg INK 4) IS MISSING OR MUTATED
-
WHAT GENES ARE ACTIVATED/INACTIVATED IN MOST COLON CANCERS
-
WHERE IS GLYCOGEN STORED?
MOSTLY IN LIVER AND MUSCLE
MOST CONCENTRATED IN LIVER BUT MORE TOTAL IN MUSCLE
-
SYNTHESIS OF GLYCOGEN
REQUIRES UDP-GLUCOSE TO ADD GLUCOSE TO GROWING GLYCOGEN CHAIN
- UDP-GLUCOSE PHOSPHORYLASE REACTION:
- GLUCOSE 1-PHOS + UTP --> UDP-GLUCOSE
GLUCOSE 1-PHOS GENERATED BY PHOS-GLUC-MUTASE FROM GLUC-6-PHOS
-
GENERATION OF GLYCOGEN BRANCH POINTS
NEED AT LEAST 11 LINEAR RESIDUES FIRST
THEN BREAK AN a1,4 LINK AND TRANSFER TO A #6 INTERNAL C
-
FATE OF GLUCOSE 1-PHOS AND GLUCOSE IN LIVER AND MUSCLE
- LIVER
- CONVERTS G-1-P TO G-6-P VIA PHOS-GLUC-MUTASE. THEN G-6-P TO GLUC VIA G-6-PHOSPHATASE FOR USE IN OTHER TISSUES
- MUSCLE:
- DOES NOT RELEASE GLUCOSE (LACKS G-6-PHOSPHATASE).
- G-1-P TO G-6-P VIA PHOS-GLUC-MUTASE THEN GLYCOLYSIS
-
ROLE OF GLYCOGENIN
PROTEIN CORE OF GLYCOGEN POLYMER
#1C OF FIRST GLUCOSE ATTACHED COVALENTLY TO HYDROXYL OF TYROSINE ON GLYCOGENIN. USES UDP-GLUCOSE
GLYCOGEN SYNTHASE THEN TAKES OVER AFTER INITIAL RESIDUES ARE ADDED
-
STEPS OF GLYCOGENOLYSIS
GLYCOGEN PHOSPHORYLASE STOPS AT 4TH GLUCOSE FROM BRANCH POINT
DEBRANCHING ENZYME TRANSFERASE REMOVES 3 GLUC FROM BRANCH AND MOVES TO MAIN STRAND
a1,6-GLUCOSIDASE BREAKS THE 1 BRANCHING GLUCOSE
-
GLYCOGENOLYSIS (GLYCOGEN BREAKDOWN)
1) GLUCAGON & EPI INC cAMP, WHICH ACTIVATES PKA. PKA PHOSES GLYCOGEN PHOSPHORYLASE KINASE (ACTIVATION), WHICH PHOSES GLYCOGEN PHOSPHORYLASE (ACTIVATION).
3) PKA ALSO INHIBITS PROTEIN PHOSPHORYLASE, KEEPING ENZYMES ACTIVE
4) INSULIN INHIBITS GLYCOGEN PHOSPHORYLASE KINASE AND GLYCOGEN PHOSPHORYLASE BY ACTIVATING PROTEIN PHOSPHATASE
- 5) LOCAL ALLOSTERIC CONTROL:
- Ca++ ACTIVATES PHOSPHORYLASE KINASE
- AMP ACTIVATES PHOSPHORYLASE
- GLUCOSE INHIBITS PHOSPHORYLASE
WHEN MUSCLES FIRST CONTRACT, INC Ca++ AND AMP SIGNAL NEED FOR ENERGY
-
STEPS FOR GLYCOGEN SYNTHESIS
1) GLUCAGON & EPI INHIBIT SYNTHESIS BY PHOS OF GLYCOGEN SYNTHASE
2) Ca++ INHIBITS SYNTHESIS BY ACTIVATING CALMODULIN KINASE, WHICH PHOSES GLYCOGEN SYNTHASE
3) INSULIN ACTIVATES PHOSPHOPROTEIN PHOSPHATASE WHICH INC GLYCOGEN SYNTHASE. INHIBITS GLYCOGEN SYNTHASE KINASE (GSK) --> INC GLYCOGEN SYNTHASE
- 4) ALLOSTERIC CONTROL:
- GLUC-6-PHOS INC GLYCOGEN SYNTHASE
-
PKA IN GLYCOGEN SYNTHESIS
PHOSES REGULATORY PROT G CAUSING PROT PHOSPHATASE TO DISSOCIATE FROM G AND LOSE ACTIVITY
PKA ALSO PHOSES INHIBITOR PROT I CAUSING IT TO BIND AND FULLY INACTIVATE PHOSPHATASE
INSULIN REVERSES BY CAUSING DEPHOS OF G CAUSING REJOINING OF G AND ACTIVATION
-
TYPE I GLYCOGEN STORAGE DISEASE
HYPOGLYCEMIA - LIVER/KIDNEYS CAN'T RELEASE GLUCOSE
HYPERLIPEMIA AND KETOSIS - FATTY ACID MET IS INCREASED
BLOOD PYRUVATE AND LACTATE INC BECAUSE FLOOD GLYCOLYSIS WITH GLUC-6-PHOS
NEED TO PROVIDE GLUC
-
TYPE II GLYCOGEN STORAGE DISEASE
CERTAIN AMOUNT OF GLYCOGEN GETS INTO LYSOSOMES
NORMALLY a1,4 GLUCOSIDASE DEGRADES
IF DEFICIENT, LYSOSOME BECOMES ENGORGED WITH GLYCOGEN RESULTING IN TOXICITY
-
TYPE III & IV GLYCOGEN STORAGE DISEASES
- III
- DEBRANCHING ENZYME DEFICIENCY, THE GLUCOSIDASE
CANNOT FULLY MET GLYCOGEN
- IV
- BRANCHING ENZYME DEFECT. GENERATION OF LONG GLYCOGEN POLYMERS DAMAGE HEPATOCYTES
-
TYPE V & VI GLYCOGEN STORAGE DISEASES
PHOSPHORYLASE DEFECTS
McARDLE'S - INITIAL EXERCISE IS INHIBITED, INDICATED BY HIGH MUSCLE ADP (CAN'T GENERATE ATP EFFICIENTLY). DEMONSTRATES REQUIREMENT OF MUSCLE GLYCOGEN AT BEGINNING OF EXERCISE. BODY ADJUSTS THROUGH BLOOD-BORNE GLUCOSE RELEASE
-
HEME SYNTHESIS FROM BEGINNING TO RING FORMATION (1-4)
- 1) SUCC-CoA + GLYCINE + ALA SYNTHASE --> ALA ACID
- MITOCHONDRIA AND RATE LIMITING STEP
- 2) 2 ALA ACIDS + ALA DEHYDROGENASE --> PORPHOBILINOGEN (CONTAINS PYRROLE RING)
- CYTOSOL
3) 4 PORPHOBILINOGEN + UROPORPHYRINOGEN I SYNTHASE --> HYDROXYMETHYLBILANE. BREAKS DOWN TO TOXIC UROPORPH I. MUST FURTHER CONVERT
4) HYDROXYMETHYLBILANE + UROPORPHYRINOGEN III COSYNTHASE --> UROPORPHYRINOGEN III. FLIPPING ONE PYRROLE RING DURING CYCLIZATION MAKES URO III INSTEAD OF URO I
-
LAST STEPS OF HEME SYNTHESIS FROM CYCLIZATION (5-8)
- 5) URO III + URO DECARB --> COPROPORPHYRINOGEN III.
- ALL ACETYL GROUPS DECARBED INTO METHYL GROUPS. COPROPOR MOVES INTO MITOCHONDRIA
- 6) COPROPOR III + COPROPOR OXIDASE --> PROTOPORPHYRINOGEN IX.
- 2 PROPIONYLS CONVERTED TO VINYL (CH=CH2)
- 7) PROTOPORPHYRINOGEN IX + PROTOPOR OXIDASE --> PROTOPORPHYRIN IX.
- DOUBLE BONDS IN RINGS MOVE BETWEEN SIDE CHAINS.
8) PROTOPORPHYRIN IX + FERROCHELATASE --> HEME. Fe ADDED TO RING
-
ALA SYNTHASE 1 vs. 2
1 FOUND IN NON-ERYTHROID CELLS
2 IN ERYTHROIDS
-
REGULATION OF HEME IN ERYTHROID CELLS
A) Fe INDUCES HEME SYNTHESIS. 5'UTR OF mRNA FOR ALA 2 HAS SEGMENT WHICH BINDS Fe-BINDING PROTEIN (STABILIZES), BUT ONLY WHEN Fe IS PRESENT
B) EXCESS HEME INHIBITS Fe UPTAKE. DIETARY Fe TRANSPORTED IN BLOOD BY TRANSFERRIN (LIGAND FOR RECEPTOR LETTING Fe INTO CELL). HEME INHIBITS (A)
C) HEME AND GLOBIN ARE BALANCED. HEME INHIBITS A KINASE THAT ACTS ON eIF2. eIF2 THUS UNPHOSED AND INC GLOBIN SYNTH.
GLOBIN COMBINES WITH HEME, SO HEME [] DROPS, THUS PHOSING eIF2 AND INHIBITING GLOBIN SYNTH
-
REGULATION OF HEME IN NON-ERYTHROID CELLS
A) HEME INHIBITS TRANSPORT OF ALA SYNTHASE 1 INTO MITOCHONDRIA (MAJOR CAUSE)
B) HEME INHIBITS SYNTH OF ALA SYNTHASE 1
C) HEME ALLOSTERICALLY INHIBITS ALA (NOT PHYSIOLOGICALLY IMPORTANT...?) SYNTHASE 1
-
RETICULOENDOTHELIAL (RE) SYSTEM
HEME DEGRADATION AND IMMUNE SYSTEM
MACROPHAGES, MONOCYTES, AND KUPFFER CELLS IN LIVER
RE ISOZYME OF HEME OXIGENASE INDUCED BY HEME, TIN, COBALT, OR STRESS
ASIDE FROM RE ISOZYME, 2 OTHERS IN BRAIN AND TESTES
C0 AS BYPRODUCT
-
WHAT IS PORPHYRIA
FAMILY OF DISEASES WHICH ARISE FROM LESIONS IN HEME BIOSYNTH PATHWAY
CAUSED BY ACCUMULATION OF INTERMEDIATES
NO PORPHYRIAS CAUSED BY DEFECT IN ALA SYNTHASE GENE
-
X-LINKED ANEMIA
ALA SYNTHASE PORPHYRIA
RARE
LESIONS IN ALA SYNTHASE
NOT ENOUGH HEME --> LESS HEME FEEDBACK CONTROL OF ALA SYNTHASE --> HIGH ALA SYNTHASE
-
ALA DEHYDROGENASE PORPHYRIA
VERY RARE
ABDOMINAL AND NEUROLOGICAL
BUILD-UP OF dALA
VERY SUSCEPTIBLE TO LEAD POISONING
-
ACUTE INTERMITTEN PORPHYRIA
PORPHOBILINOGEN DEAMINASE
ONE OF MOST FREQUENT
LESSENED ACTIVITY OF PB DEAMINASE RESULTING IN INC PB AND dALA
ABDOMINAL AND NEUROLOGICAL
SOME PSYCHOSIS
-
CONGENITAL ERYTHROPOIETIC PORPHYRIA
UROPOR-GEN III COSYNTHASE
VERY RARE
ACCUMULATION OF UROPOR-GEN I, UROPORPHYRIN I, COPOR-GEN I, AND COPROPORPHYRIN I
PHOTOSENSITIVITY, DISCOLORED URINE, PIGMENTS IN TEETH
-
PORPHYRIA CUTANEA TARDA
UROPORPHYR-GEN DECARB
MOST COMMON
ACCUMULATION OF UROPORPHYRIN III
SYMPTOMS LARGELY IN SKIN
MAY BE INDUCED BY HEXACHLOROBENZENE
TREAT WITH CHLOROQUIN AND PHLEBOTOMY
-
HEREDITARY COPROPORPHYRIA
COPROPOR-GEN OXIDASE
RARE
ACCUMULATION OF COPROPORPHYRIN III
NEUROLOGICAL AND ABDOMINAL
SOMETIMES INVOLVES SKIN
-
VARIEGATE PORPHYRIA
PROTOPORPHYRINOGEN OXIDASE
ACCUMULATION OF SEVERAL PORPHYRINS
SKIN LESSIONS
SOME ABDOMINAL AND NEUROLOGICAL
-
ERYTHROPOIETIC PROTOPORPHYRIA
FERROCHELATASE
PHOTOSENSITIVITY
ACCUMULATION OF PORPHYRINS IN SKIN
-
LEAD POISONING
SOME SYMPTOMS OF PORPHYRIA
SOME ENZYMES IN HEME SYTH INHIBITED BY LEAD (dALADEHYDE AND FERROCHELATASE)
ENZYMES HAVE SULFHYDRYL GROUPS THAT REACT WITH HEAVY METALS
-
ETIOLOGY OF PORPHYRIA SYMPTOMS (4)
ABDOMINAL - BUILD-UP OF TOXIC INTERMEDIATES AND BY-PRODUCTS IN LIVER CAUSE PAIN
NEUROLOGICAL - BUILD-UP IN BRAIN CAUSES PSYCH BEHAVIOR AND/OR NEURO SYMPTOMS
SKIN - BUILD-UP IN SKIN, REACTIONS WITH ULTRA-VIOLET LIGHT MAKE FREE RADICALS
TEETH - BUILD-UP CAUSES DISCOLORATION AND BRITTLE TEETH
-
DRUG INTERACTION IN PORPHYRIAS
CERTAIN TYPES AGGRAVATED BY CERTAIN DRUGS SUCH AS PHENOBARBITAL
INDUCE LIVER TO MAKE CYTOCHROME P450 WHICH CONTAINS HEME, AND MAKE HEME ITSELF
ACCUMULATION OF TOXIC INTERMEDIATES
MUST PROPERLY DIAGNOSE PATIENT BEFORE TREATMENT
-
PUBERTY AND PORPHYRIA
SYMPTOMS DUE NOT APPEAR UNTIL PUBERTY
INC SEX HORMONES AND INCREASE ACTIVITY/AMOUNT OF ENZYMES (CYTOCHROME P450)
PUBERTY INDUCES HEME SYNTH WHICH CAUSES ACCUMULATION IN THOSE WITH LESIONS IN HEME SYNTH PATHWAYS
-
HEMOLYTIC JAUNDICE
EXCESS ERYTH DESTRUCTION
HIGH BIL-ALB, HIGH EXCRETION
-
CIRRHOSIS, INFECTIOUS HEP (JAUNDICE)
LIVER DAMAGE SO LESS REACTION OF BILIRUBIN WITH GLUCURONOSIDE
HIGH BIL-ALB, LOW BIL EXCRETION, LOW BIL-GLUCURONIDE
-
NEONATAL JAUNDICE
IMMATURE LIVER
SIMILAR BILIRUBIN METABOLISM TO CIRRHOSIS AND HEP
TEMPORARY
TREAT WITH UV RAD TO DESTROY EXCESS BIL
HIGH BIL-ALB, LOW EXCRETION
-
CRIGLER-NIJJAR SYNDROME TYPE I
RARE JAUNDICE
COMPLETE LOSS OF UDP-GLUCUNOSYLTRANSFERASE ACTIVITY
BIL DISTRIBUTION SIMILAR TO CIRRHOSIS AND HEP, BUT MORE EXTREME
FATAL IF LEFT UNTREATED
UV RAD FOR TREATMENT OR LIVER TRANSPLANT
HIGH BIL-ALB, LOW EXCRETION
-
CRIGLER-NAJJAR SYNDROME TYPE 2
JAUNDICE
UDP-GLURUNOSYLTRANSFERASE ACTIVITY DOWN 90%
ENCEPHALOPATHY IF UNTREATED
TREAT WITH PHENOBARBITAL - INDUCES UDP-GLURUNOSYLTRANSFERASE SYNTHESIS
-
GILBERT SYNDROME
JAUNDICE
UDP-GLURUN-ASE ACTIVITY IS DOWN 50%
BEGNIGN CONDITION & IN 10% OF POPULATION
TREAT WITH PHENOBARBITAL
-
OBSTRUCTIVE JAUNDICE
JAUNDICE
OBSTRUCTION PREVENTS BILE FROM REACHING INTESTINE
BIL-GLUCURONOSIDE IS HIGH, BIL-ALB NORM, EXCRETION LOW
|
|