Concepts in Anatomy & Physiology PDF

Concepts in Anatomy & Physiology MPAS 5003 Cell Structure and Function Overview of Content § Nucleus structure § D N A / chrom atin s tructure § Protein synthesis and gene expression § Cell cycle § Cell growth § Mitosis § Control of growth / dev elopm ent § L...

Concepts in Anatomy & Physiology MPAS 5003 Cell Structure and Function Overview of Content § Nucleus structure § D N A / chrom atin s tructure § Protein synthesis and gene expression § Cell cycle § Cell growth § Mitosis § Control of growth / dev elopm ent § Lo ss of control / -plas ia § Uncontrolled g rowth / cancer  Concepts in Anatomy & Physiology Cell Nucleus MPAS 5003 Chemistry and Biochemistry Nucleus ▪ Structure: ▪ Membrane = phospholipid bilayer ▪ Membrane pores ▪ Endoplasmic reticulum ▪ Nucleoplasm ▪ Chromatin (DNA) ▪ Nucleolus ▪ Ribosome production Chromatin Chromosomes ▪ 22 pairs + XX/XY Chromatin Histones DNA ▪~ 3 billion base pairs ▪ ~ 2 meters long in most cells ▪ ~ 30,000 genes encoding about 100,000 proteins ( ~ 1 % ) ▪9 9 % : ▪ regulatory ▪ structural ▪? Cell Differentiation ▪ Embryonic cells are largely undifferentiated (“unspecialized”) ▪ Com plex chem ical / protein signals guide development of organs/structures ▪ Cells differentiate – become specialized ▪ Each cell only produces a small subset of the ~ 3 0 , 0 0 0 possible proteins encoded in the DNA Gene Expression: Regulating Protein Synthesis A Basic Overview of Protein Synthesis Gene Expression: Regulation of Protein Synthesis Multiple factors control expression of a particular gene: § Epigenetics § Histone interactions – open v s closed chromatin § Methylation § Acetylation Gene Expression: Regulation of Protein Synthesis Multiple factors control expression of a particular gene § Promoters Gene Expression: Regulation of Protein Synthesis Multiple factors control expression of a particular gene § Enhancers/Activators v s Repressors/Silencers Gene Expression: Regulation of Protein Synthesis Protein Synthesis Protein Synthesis ▪mRNA transcript is highly processed before translation ▪ Introns removed – “splicing” ▪ Cap and tail added Protein Synthesis ▪ Multiple different proteins made from s am e m R N A ▪ Alternative splicing Protein Synthesis Translation extensively controlled by R N A Protein Synthesis Non-coding RNA in disease Revised Model Cell Cycle Revised Model § Divided into interphase and mitosis § Interphase divided into three phases § G 1 – cell growth § S – D N A replication § G 2 – mitosis preparation § G 0 – cells not undergoing mitosis Revised Model § Cell cycle checkpoints § Quality control § Locations § Late G 1 – ready for replication § S phase / G 2 – D N A damage control § M phase – final check on chromosome prepping Cell Cycle § Cell cycle control § Two major proteins § Cyclin-dependent kinases (CDK) § Always present § Has to bind cyclin protein to potentially be active § Cyclins § Made in response to appropriate signals for division Cell Cycle ▪ Cell cycle control ▪ Cyclin-CDK complex ▪ Highly regulated by other molecules ▪ Inhibitors ▪ Activators Cell Cycle Phases Cell Cycle: G1 Cell Growth ▪ Preparation for cell division ▪ Cell size increases ▪ Organelles replicated ▪ Protein synthesis – proteins involved in cell division ▪ Triggers ▪ Growth factors ▪ Inhibitors ▪ Lack of needed molecules – nucleotides, amino acids, ATP, etc Cell Cycle: G1 Cell Growth ▪ G1/S checkpoint ▪ Major checkpoint – point of no return for mitosis ▪ Cyclin D ▪ Rb protein ▪ E2F transcription factors Cell Cycle: S – DNA Replication ▪ Genome copied ▪ D N A strands duplicated ▪ Histones duplicated and chromatin reformed at site of D N A replication ▪ Epigenetic modifications re- established Cell Cycle: S – DNA Replication ▪ Checkpoints ▪ D N A damage and repair ▪ Cyclin A Cell Cycle: S – DNA Replication ▪ Types of mutations: ▪ Gene mutations ▪ Substitution (point mutation) ▪ Change in amino acid ▪ Formation of a stop codon ▪ Insertion ▪ Deletion ▪ Duplication Cell Cycle: S – DNA Replication ▪ Types of mutations: ▪ Chromosome mutations ▪ Deletions ▪ Duplications ▪ Inversions Cell Cycle: G2 Preparation for Division ▪ Second growth phase ▪ Protein synthesis for mitosis ▪ G2/M checkpoint ▪ Cyclin B /C D K 1 ▪ D N A repair ▪ p5 3 Cell Cycle: Mitosis (M) ▪ Chromatin condenses into chromosomes (2 chromatids) ▪ Nuclear membrane breaks down ▪ Chromosomes align along midline ▪ Chromatids separated and pulled to opposite sides ▪ Formation of nucleus and cytokinesis Cell Cycle: Mitosis (M) ▪ Checkpoint ▪ M etaphas e  Cell Cycle Dysregulation and Cancer Terminology § “-plasia” – growth / developm ent § M etaplasia - replacem ent / conversion § Dysplasia – abnormal appearance § Hyperplasia – increased number § Neoplasia – abnormal proliferation § Aplasia / Hypoplasia – lack of / decreased # § “-trophy” – growth / nutrition § Hypertrophy – increased volume § Atrophy – decreas e / los s Metaplasia Dysplasia Apoptosis ▪ Intrinsicvs extrinsic pathways ▪ Caspases Apoptosis  Development of Cancer: Dysplasia to Hyperplasia Development of Cancer Schematic depiction of the clonal evolution of cancer. Mutations occur stochastically in the tissue. While many are inconsequential, some can contribute to a proliferative phenotype that can expand to form a subclone. Additional mutations within this subclone can confer higher proliferative potential, and sequential cycles of such growth-promoting mutations can eventually repopulate the tissue, creating a genetic field defect in a normal-appearing tissue. Ultimately, mutations that promote continued growth beyond tissue boundaries can lead to the formation of a tumor with morphological and clinical consequences. Development of Cancer ▪ Neoplasia involves disruption in (typically) multiple processes ▪ Ch a n g e s in D N A sequence leads to: ▪ Changes in chromatin structure (epigenetics) ▪ C h a n g e s in chromosome # ▪ Activation of telomerase ▪ C h a n g e s in cell-cell signaling pathways ▪ Dysregulation of cell cycle checkpoints ▪ Dysregulation of gene expression ▪ Evasion of apoptosis ▪ Loss of stromal influence on growth ▪ C h a n g e s in metabolism to support excess growth ▪ Evasion of the immune system  Development of Cancer: Oncogenesis and Tu m o r S u p p r e s s o r Genes Oncogenes ▪ Genesthat confer a growth advantage thru gain-of- function mutations ▪ Examples ▪ EGFR – growth factor receptor – stuck in the “on” position ▪ KRAS/NRAS/HRAS – cell signaling for growth – stuck “on” ▪ MYC – transcription factor – overexpression ▪ miRNA ▪ Only need mutation on one chromosome to get gain-of- function Tumor Suppressor Genes ▪ Genesthat confer a growth advantage thru loss-of- function mutations ▪ Need mutations in both copies to fully confer advantage ▪ Examples ▪ P53 and RB1- Cell cycle checkpoint regulator/DNA repair ▪ MLH1, BRCA1, and BRCA2 – D N A repair ▪ APC – cell adhesion ▪ PTEN – cell signaling Development of Cancer Development of Cancer ▪ Neoplasia involves disruption in (typically) multiple processes ▪ Ch a n g e s in D N A sequence leads to: ▪ Changes in chromatin structure (epigenetics) ▪ C h a n g e s in chromosome # ▪ Activation of telomerase ▪ C h a n g e s in cell-cell signaling pathways ▪ Dysregulation of cell cycle checkpoints ▪ Dysregulation of gene expression ▪ Evasion of apoptosis ▪ Loss of stromal influence on growth ▪ C h a n g e s in metabolism to support excess growth ▪ Evasion of the immune system Development of Cancer Telomerase activation Development of Cancer ▪ Changes in cell-cell signaling ▪ Growth factor receptor oncogenes ▪ Cell signaling oncogenes Development of Cancer ▪ Changes in cell-cell signaling ▪ Cell signaling tumor suppressor Development of Cancer ▪ Evasion of apoptosis ▪ Loss of BCL protein function Development of Cancer ▪ Changes in metabolism ▪ Angiogenesis Development of Cancer ▪ Changes in metabolism ▪ Angiogenesis ▪ Glucose metabolism Development of Cancer ▪ Cancers are heterogenous mix of cells with varying mutations ▪ Implication for treatment Development of Cancer ▪ Mechanism of D N A damage: ▪ UV light ▪ Toxins ▪ Smoking!! ▪ Viruses ▪ Radiation Classification of Neoplasms Classification of Neoplasms ▪ “-oma” ▪ Benign tumors often named for the type of tissue that is overgrown ▪ Examples: ▪ Lipoma ▪ Adenoma ▪ Osteoma ▪ Malignant tumors (cancers) named initially after the embryonic tissue they are derived from and from the organ of origin ▪ Carcinoma – ectoderm and endoderm ▪ Subtypes: ▪ S q u a mo u s cell carcinoma - ectoderm ▪ Adenocarcinoma - endoderm ▪ Sarcoma - mesoderm Classification of Neoplasms ▪ Embryonic tissues: ▪ Ectoderm – skin, nervous system, pituitary ▪ Endoderm – linings of lungs/digestive, glands ▪ Mesoderm – blood, muscle, kidneys, bone, cartilage (“mesenchyme”) Classification of Neoplasms § General groupings: § N euroendocrine § Epithelial neoplasms neoplasms § Carcinoid tumors § skin, linings, etc § Carcinoid syndrome § M esenchy m al neoplasms § Germ cell line neoplasms § Harder to characterize § Differentiation into all § Hematologic neoplasms types of cells § Gene translocations (teratomas) Cancer Staging Tumor staging Solid tumors § T M N sy stem § Tumor-node-metastasis Breast § Tum or cancer § Size and extent § N ode § Extent of metastasis to lymph nodes § Metastasis § Presence of distant metastasis § Different tumors have different numbering systems Colon cancer Tumor staging ▪ Prognostic staging ▪ TNM staging groups divided into 4 prognostic groups ▪ Stage I – excellent prognosis ▪ Stage IV – very poor prognosis Tumor staging ▪ TNM system is hard to use when talking to patients – prognostics are always easier ▪ Each cancer has its own staging system ▪ Ex - CLL  Concepts in Anatomy & Physiology Questions: [email protected] MPAS 5003 Chemistry and Biochemistry