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Transcript
Hormones and Signal Transduction III Dr. Kevin Ahern RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) EGFR Signaling, Part 1 RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) EGFR Signaling, Part 1 EGFR Dimer RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) EGFR Signaling, Part 1 EGFR Dimer Autophosphorylated Tyrosines in Cytoplasmic Domain RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) EGFR Signaling, Part 1 EGFR Dimer Autophosphorylated Tyrosines in Cytoplasmic Domain Signaling Complex Assembled on Phosphotyrosines RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) EGFR Signaling, Part 1 EGFR Dimer Autophosphorylated Tyrosines in Cytoplasmic Domain Signaling Complex Assembled on Phosphotyrosines GTP GDP RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) EGFR Signaling, Part 1 EGFR Dimer Autophosphorylated Tyrosines in Cytoplasmic Domain Signaling Complex Assembled on Phosphotyrosines GTP GTP GDP RTKs -‐ Epidermal Growth Factor Epidermal Growth Factor Receptor (EGFR) EGFR Signaling, Part 1 EGFR Dimer Autophosphorylated Tyrosines in Cytoplasmic Domain Signaling Complex Assembled on Phosphotyrosines GTP GTP GDP Prepares Cell for Division RTKs -‐ Epidermal Growth Factor RTKs -‐ Epidermal Growth Factor RAS Activates RAF Kinase RTKs -‐ Epidermal Growth Factor RAS Activates RAF Kinase RAF/RAS Activates MEK Kinase RTKs -‐ Epidermal Growth Factor RAS Activates RAF Kinase RAF/RAS Activates MEK Kinase MEK Activates MAP Kinase Cascade RTKs -‐ Epidermal Growth Factor RAS Activates RAF Kinase RAF/RAS Activates MEK Kinase MEK Activates MAP Kinase Cascade Transcription Factor Phosphorylation Activates Gene Expression RAS RAS RAS is a Family of Related Proteins RAS RAS is a Family of Related Proteins Each is Monomeric and like the α-subunit of G-Proteins RAS RAS is a Family of Related Proteins Each is Monomeric and like the α-subunit of G-Proteins RAS Proteins Bind Guanine Nucleotides RAS RAS is a Family of Related Proteins Each is Monomeric and like the α-subunit of G-Proteins RAS Proteins Bind Guanine Nucleotides Human r-RAS RAS RAS is a Family of Related Proteins Each is Monomeric and like the α-subunit of G-Proteins RAS Proteins Bind Guanine Nucleotides Human r-RAS Bound GDP RAS RAS is a Family of Related Proteins Each is Monomeric and like the α-subunit of G-Proteins RAS Proteins Bind Guanine Nucleotides RAS Swaps GDP for GTP on Activation Human r-RAS Bound GDP RAS RAS is a Family of Related Proteins Each is Monomeric and like the α-subunit of G-Proteins RAS Proteins Bind Guanine Nucleotides RAS Swaps GDP for GTP on Activation RAS Slowly Cleaves GTP to GDP Human r-RAS Bound GDP RTKs Summary RTKs Summary Dimerization is Important for RTK Activation RTKs Play Important Roles in Regulating Cell Proliferation Binding of Ligand Causes Dimerization for Most RTKs Dimerization Causes Cytoplasmic Tails to Autophosphorylate and Activate A Signaling Complex Binds to Phosphotyrosines and Communicates Message to Cell (usually by phosphorylation) The Insulin Receptor is a RTK that Stimulates Movement of GLUT4 to Membranes Insulin Signaling Stimulates Phosphoprotein Phosphatase Phosphoprotein Phosphatase Reverses Effects of Epinephrine Insulin Signaling Favors Reduced Blood Glucose and Glycogen Synthesis Epinephrine Signaling Favors Increased Blood Glucose and Glycogen Breakdown EGFR Dimerizes and Activates on Binding EGF EGF Signaling Activates Transcription and Favors Cell Division RAS is Like a G-Protein and Activates Cell Division When Bound to GTP Turning off EGFR Signaling Involves GTPase (Ras), Phosphatases, and Endocytosis of Receptors Steroid Hormone Signaling Steroid Hormone Signaling Steroid Hormones Control Metabolism, Inflammation, Immune Functions, Water/salt Balance, Sexual Characteristics, and Response to Illness/Injury Steroid Hormone Signaling Steroid Hormones Control Metabolism, Inflammation, Immune Functions, Water/salt Balance, Sexual Characteristics, and Response to Illness/Injury Steroid Signaling Uses Intracellular, Non-membrane Receptors Steroid Hormone Signaling Steroid Hormones Control Metabolism, Inflammation, Immune Functions, Water/salt Balance, Sexual Characteristics, and Response to Illness/Injury Steroid Signaling Uses Intracellular, Non-membrane Receptors Five Classes of Steroid Hormones in Two Groups - Corticosteroids and Sex Hormones Steroid Hormone Signaling Steroid Hormones Control Metabolism, Inflammation, Immune Functions, Water/salt Balance, Sexual Characteristics, and Response to Illness/Injury Steroid Signaling Uses Intracellular, Non-membrane Receptors Five Classes of Steroid Hormones in Two Groups - Corticosteroids and Sex Hormones Signaling Mostly Affects Gene Expression so Tends to be Slower in its Effects Steroid Hormone Signaling Steroid Hormone Signaling Steroid Hormone Released into Blood Steroid Hormone Signaling Steroid Hormone Released into Blood Crosses Lipid Bilayer of Target Cell Steroid Hormone Signaling Steroid Hormone Released into Blood Crosses Lipid Bilayer of Target Cell Binds to Internal Receptor Steroid Hormone Signaling Steroid Hormone Released into Blood Crosses Lipid Bilayer of Target Cell Binds to Internal Receptor Internal Receptor Changes Shape, Becoming Transcription Factor Steroid Hormone Signaling Steroid Hormone Released into Blood Crosses Lipid Bilayer of Target Cell Binds to Internal Receptor Internal Receptor Changes Shape, Becoming Transcription Factor Transcription Factor Alters Cell’s Gene Expression Steroid Hormone Signaling Nucleus Cell Steroid Hormone Signaling Nucleus Lipid Bilayer Cell Steroid Hormone Signaling Receptor Bound to Hsp70 Nucleus Lipid Bilayer Cell Steroid Hormone Signaling 1. Hormone Arrives in Blood Receptor Bound to Hsp70 1 Nucleus Lipid Bilayer Cell Steroid Hormone Signaling 2. Movement Across Lipid Bilayer 1. Hormone Arrives in Blood 2 Receptor Bound to Hsp70 1 Nucleus Lipid Bilayer Cell Steroid Hormone Signaling 3. Hormone Binds Receptor, Hsp70 2. Movement Across Lipid Bilayer Released 1. Hormone Arrives in Blood Receptor Bound to Hsp70 2 1 3 Nucleus Lipid Bilayer Cell Steroid Hormone Signaling 3. Hormone Binds Receptor, Hsp70 2. Movement Across Lipid Bilayer Released 4. Movement of Hormone-bound Receptor to Nucleus 1. Hormone Arrives in Blood Receptor Bound to Hsp70 2 1 3 Nucleus 4 Lipid Bilayer Cell Steroid Hormone Signaling 5. Hormone-bound Receptor Binds DNA, Initiates Transcription 3. Hormone Binds Receptor, Hsp70 2. Movement Across Lipid Bilayer Released 4. Movement of Hormone-bound Receptor to Nucleus 1. Hormone Arrives in Blood Receptor Bound to Hsp70 2 1 5. Transcription 3 Nucleus 4 Lipid Bilayer Cell Steroid Hormone Signaling Glucocorticoid Hormone Signaling Hormone Entry Steroid Hormone Signaling Glucocorticoid Hormone Signaling HSP Release Hormone Entry Steroid Hormone Signaling Glucocorticoid Hormone Signaling HSP Release Hormone Entry Dimerization Steroid Hormone Signaling Glucocorticoid Hormone Signaling HSP Release Hormone Entry Steroid Hormone Signaling Dimerization Movement to Nucleus Glucocorticoid Hormone Signaling HSP Release Hormone Entry Steroid Hormone Signaling Dimerization Movement to Nucleus Transcription Activation Glucocorticoid Hormone Signaling Hormones and Signal Transduction • Non-Hormone Signaling Hormones and Signal Transduction • Non-Hormone Signaling Cells Communicate in Other Ways Than With Hormones Hormones and Signal Transduction • Non-Hormone Signaling Cells Communicate in Other Ways Than With Hormones Nerve Transmission Hormones and Signal Transduction • Non-Hormone Signaling Cells Communicate in Other Ways Than With Hormones Nerve Transmission Relies on Ion Gradients and Neurotransmitter Molecules to Transmit Signal Hormones and Signal Transduction • Non-Hormone Signaling Cells Communicate in Other Ways Than With Hormones Nerve Transmission Relies on Ion Gradients and Neurotransmitter Molecules to Transmit Signal Blocked by Ion Channel Blocking Molecules Hormones and Signal Transduction • Non-Hormone Signaling Cells Communicate in Other Ways Than With Hormones Nerve Transmission Relies on Ion Gradients and Neurotransmitter Molecules to Transmit Signal Blocked by Ion Channel Blocking Molecules Prostanoids Hormones and Signal Transduction • Non-Hormone Signaling Cells Communicate in Other Ways Than With Hormones Nerve Transmission Relies on Ion Gradients and Neurotransmitter Molecules to Transmit Signal Blocked by Ion Channel Blocking Molecules Prostanoids Derived from Arachidonic Acid and Exert Effects Near Where They are Released Prostaglandins, Prostacyclin and Thromboxanes Prostaglandin H2 Thromboxane A2 Hormones and Signal Transduction • Non-Hormone Signaling Cells Communicate in Other Ways Than With Hormones Nerve Transmission Relies on Ion Gradients and Neurotransmitter Molecules to Transmit Signal Blocked by Ion Channel Blocking Molecules Prostanoids Derived from Arachidonic Acid and Exert Effects Near Where They are Released Prostaglandins, Prostacyclin and Thromboxanes Synthesis Inhibited by Steroids and NSAIDs - Aspirin, Ibuprofen Prostaglandin H2 Thromboxane A2 Signaling Gone Wild • Signaling Gone Wild Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Oncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Oncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth Proto-Oncogene - Unmutated Form of an Oncogene Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Oncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth Proto-Oncogene - Unmutated Form of an Oncogene Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Oncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth Proto-Oncogene - Unmutated Form of an Oncogene Mutations in Signaling Systems Can Lead to Tumor Formation Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Oncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth Proto-Oncogene - Unmutated Form of an Oncogene Mutations in Signaling Systems Can Lead to Tumor Formation Mutations Affecting Protein Structure/Function Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Oncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth Proto-Oncogene - Unmutated Form of an Oncogene Mutations in Signaling Systems Can Lead to Tumor Formation Mutations Affecting Protein Structure/Function Mutations Affecting Expression of Protein Signaling Gone Wild • Signaling Gone Wild Signaling Proteins Play Important Roles in Growth and Division Oncogene - A Mutated Gene Whose Activity Can Cause Uncontrolled Growth Proto-Oncogene - Unmutated Form of an Oncogene Mutations in Signaling Systems Can Lead to Tumor Formation Mutations Affecting Protein Structure/Function Mutations Affecting Expression of Protein Other Mutations Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function RAS Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function 1. GDP Bound RAS Inactive RAS Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function 1. GDP Bound RAS Inactive 2. GTP Binding Activates RAS Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function 1. GDP Bound RAS Inactive 2. GTP Binding Activates 3. GTPase Converts GTP to GDP, Inactivating RAS Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function 1. GDP Bound RAS Inactive 2. GTP Binding Activates 3. GTPase Converts GTP to GDP, Inactivating 4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS RAS Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function 1. GDP Bound RAS Inactive RAS 2. GTP Binding Activates 3. GTPase Converts GTP to GDP, Inactivating 4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS 5. Activated RAS Stimulates Cell Division Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function 1. GDP Bound RAS Inactive RAS 2. GTP Binding Activates 3. GTPase Converts GTP to GDP, Inactivating 4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS 5. Activated RAS Stimulates Cell Division Mutated RAS Most Common Point Mutation in Cancer Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function 1. GDP Bound RAS Inactive RAS 2. GTP Binding Activates 3. GTPase Converts GTP to GDP, Inactivating 4. Mutations of Amino Acids 11/12 or 61 Inhibit GTPase & Activate RAS 5. Activated RAS Stimulates Cell Division Mutated RAS Most Common Point Mutation in Cancer Mutated RAS in 90% of Pancreatic Cancer and 20% of all Cancers Hormones and Signal Transduction • Signaling Gone Wild Hormones and Signal Transduction • Signaling Gone Wild Not All Tyrosine Kinases are RTKs Hormones and Signal Transduction • Signaling Gone Wild Not All Tyrosine Kinases are RTKs Src Proteins are Tyrosine Kinases Found in Various Cell Locations Src Hormones and Signal Transduction • Signaling Gone Wild Not All Tyrosine Kinases are RTKs Src Proteins are Tyrosine Kinases Found in Various Cell Locations Dephosphorylated Src Acts to Stimulate Cell Division Src Hormones and Signal Transduction • Signaling Gone Wild Not All Tyrosine Kinases are RTKs Src Proteins are Tyrosine Kinases Found in Various Cell Locations Dephosphorylated Src Acts to Stimulate Cell Division Phosphorylation of Src’s Tyrosines Turns it OFF Src Hormones and Signal Transduction • Signaling Gone Wild Not All Tyrosine Kinases are RTKs Src Proteins are Tyrosine Kinases Found in Various Cell Locations Dephosphorylated Src Acts to Stimulate Cell Division Phosphorylation of Src’s Tyrosines Turns it OFF Mutations that Affect Src’s Phosphorylation Convert Src Hormones and Signal Transduction • Signaling Gone Wild Not All Tyrosine Kinases are RTKs Src Proteins are Tyrosine Kinases Found in Various Cell Locations Dephosphorylated Src Acts to Stimulate Cell Division Phosphorylation of Src’s Tyrosines Turns it OFF Mutations that Affect Src’s Phosphorylation Convert it to an Oncogene Src Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function Src Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function Src Src Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function Phosphorylated Tyrosines Block Access to its SH2 Domain and Prevent it From Participating in Signaling Leaving it Inactive Src Src Hormones and Signal Transduction • Signaling Gone Wild Mutations Affecting Protein Structure/Function Phosphorylated Tyrosines Block Access to its SH2 Domain and Prevent it From Participating in Signaling Leaving it Inactive Src Mutations Changing These Tyrosines Leave the Protein Always Activated, Stimulating Uncontrolled Cell Division Src Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Mutations Increasing Levels of HER2 Found in Several Cancers Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Mutations Increasing Levels of HER2 Found in Several Cancers Breast Cancer (15-30%) Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Mutations Increasing Levels of HER2 Found in Several Cancers Breast Cancer (15-30%) Ovarian Cancer Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Mutations Increasing Levels of HER2 Found in Several Cancers Breast Cancer (15-30%) Ovarian Cancer Stomach Cancer Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Mutations Increasing Levels of HER2 Found in Several Cancers Breast Cancer (15-30%) Ovarian Cancer Stomach Cancer Uterine Cancer Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Mutations Increasing Levels of HER2 Found in Several Cancers Breast Cancer (15-30%) Ovarian Cancer Stomach Cancer Uterine Cancer Treated with Monoclonal Antibody - Herceptin Hormones and Signal Transduction • Introduction Mutations Affecting Expression of Protein HER2-Herceptin Complex HER2 Doesn’t Require EGF Binding for Dimerization/Activation Is Always Signaling Cell to Divide When Dimerized Mutations Increasing Levels of HER2 Found in Several Cancers Breast Cancer (15-30%) Ovarian Cancer Stomach Cancer Uterine Cancer Treated with Monoclonal Antibody - Herceptin Herceptin Binds HER2’s Extracellular Domain to Prevent Dimerization Hormones and Signal Transduction • Introduction Other Mutations Hormones and Signal Transduction • Introduction Other Mutations Bcr-Abl Fusion bcr 22 abl 9 Chromosomes 9 & 22 Hormones and Signal Transduction • Introduction Other Mutations Bcr-Abl Fusion bcr 22 Crossover abl 9 Chromosomes 9 & 22 Hormones and Signal Transduction • Introduction Other Mutations Bcr-Abl Fusion bcr bcr-abl fusion 22/9 22 abl 9 Chromosomes 9 & 22 9/22 Fusion Chromosomes Hormones and Signal Transduction • Introduction Other Mutations Bcr-Abl Fusion The bcr-abl fusion links the tyrosine kinase of abl with the N-terminus and transcription control of bcr bcr bcr-abl fusion 22/9 22 abl 9 Chromosomes 9 & 22 9/22 Fusion Chromosomes Hormones and Signal Transduction • Introduction Other Mutations Bcr-Abl Fusion The bcr-abl fusion links the tyrosine kinase of abl with the N-terminus and transcription control of bcr bcr bcr-abl fusion 22/9 22 abl 9 Chromosomes 9 & 22 9/22 Fusion Chromosomes All regulation of abl is lost in the fusion, so the bcr-abl fusion is signaling ‘division’ all the time Hormones and Signal Transduction • Introduction Hormones and Signal Transduction • Introduction Bcr-Abl Fusion Hormones and Signal Transduction • Introduction Bcr-Abl Fusion Also Known as Philadelphia Translocation Hormones and Signal Transduction • Introduction Bcr-Abl Fusion Also Known as Philadelphia Translocation Present in 95% of people with CML (Chronic Myelogenous Leukemia) Hormones and Signal Transduction • Introduction Bcr-Abl Fusion Also Known as Philadelphia Translocation Present in 95% of people with CML (Chronic Myelogenous Leukemia) Treated with Tyrosine Kinase Inhibitor - Gleevec (Imatinib) Hormones and Signal Transduction • Introduction Bcr-Abl Fusion Also Known as Philadelphia Translocation Present in 95% of people with CML (Chronic Myelogenous Leukemia) Treated with Tyrosine Kinase Inhibitor - Gleevec (Imatinib) Hormones and Signal Transduction • Introduction Bcr-Abl Fusion Also Known as Philadelphia Translocation Present in 95% of people with CML (Chronic Myelogenous Leukemia) Treated with Tyrosine Kinase Inhibitor - Gleevec (Imatinib) Gleevec has Almost Doubled the Five Year Survival Rate of CML Patients Other Signaling Considerations Other Signaling Considerations Steroid Hormone Signaling Uses Intracellular, Non-membrane Receptors Steroid Hormone Receptors Act as Transcription Factors When Bound to Hormone Non-hormone Signaling Includes Nerve Transmission and Prostanoid Signaling Src Proteins are Tyrosine Kinases Found in Various Cell Locations Nerve Transmission Involves Action Potentials Generated by Ion Gradient Changes Oncogenes Cause Cancer and are Mutated Proto-Oncogenes Mutations in Signaling Systems Can Lead to Tumor Formation RAS Mutations that Inhibit GTPase Can Cause Cancer Mutated RAS Most Common Point Mutation in Cancer Phosphorylation of Src’s Tyrosines Turns it OFF Phosphorylated Tyrosines Block Access to Src’s SH2 Domain Src’s SH2 Domain Controls Access to Other Signaling Proteins Mutations Changing Src’s Tyrosines Leave the Protein Always Activated Human EGFR (HER2) HER2 Doesn’t Require EGF Binding for Dimerization/Activation Overexpression of HER2 Linked to Many Cancers HER2 Cancers Treated with Herceptin bcr-abl Fusion links the Tyrosine Kinase of abl with N-terminus & Transcription Control of bcr bcr-abl Fusions Implicated in Many CMLs bcr-abl Tumors Fought with Tyrosine Kinase Inhibitor - Gleevec Metabolic Melody Student Nightmares (To the tune of “Norwegian Wood”) Copyright © Kevin Ahern Metabolic Melody Student Nightmares (To the tune of “Norwegian Wood”) Copyright © Kevin Ahern I answered 3 ‘b’. But then I thought. It might be ‘c’ Or was the false true? I can’t undo. It makes me blue It asked me to list all the enzymes that regulate fat As I wrote them down I discovered I didn’t know Jack I ought to give thanks, Scoring some points, filling in blanks I squirmed in my seat Feeling the heat, shuffling my feet Professor then told me there wasn’t a chance I would pass So I started crying and fell through a big pane of glass I suffered no harm, 'Cuz I awoke, to my alarm Oh nothing compares To deadly scares, of student nightmares
