Robbins Chapter 4:
Tissue Repair: Cellular Growth, Fibrosis, and Wound Healing

Repair of tissues involves regeneration (replacement of damaged cells by cells of the same type) or fibrosis (replacement by connective tissue).
Cell Cycle and Proliferative Potential
G1 - presynthetic
S - DNA synthesis
G2 - premitotic
M - mitotic

Underlying supporting stroma of the parenchymal cells (BM) necessary for organized regeneration.
Nondividing (permanent) cells - left the cell cycle and can't undergo mitotic division in postnatal life (nerve cells, skeletal and cardiac muscle)
Quiescent (stable) cells - low level of replication (most cells of body)
Continuously dividing cells - have a population of stem cells (epithelium, hematopoietic tissues)

Molecular Events in Cell Growth:
Three signaling methods: autocrine, paracrine and endocrine
Cell Surface Receptors:
· Receptors with intrinsic tyrosine kinase activity: EGF, FGF, PDGF. Dimerization leads to receptor autophosphorylation and interaction with cytolosolic proteins (ras, PI-3 kinase, phospholipase C, src).
· Receptors without intrinsic catalytic activity: cytokine receptor superfamily. Activate cytosolic protein tyrosine kinases.
· G-protein linked receptors: inflammatory chemokines and hormone receptors (epinephrine, glucagon). Have 7 transmembrane loops.

Signal Transduction Systems:
· Mitogen activated protein (MAP) kinase system:
Inactive ras binds GDP/active ras binds GTP: mutant ras binds GTP but can't hydrolyze it. Permanently "on."
Ras binds Raf, which phosphorylates MEK (a MAP kinase)
ERK (a MAP kinase) translocates to the nucleus and phosphorylates c-jun and c-fos, activating gene expression
· PI-3 kinase
Generates membrane-associated lipid mediators.
Second messengers recruit and activate intracellular kinases, e.g. Akt.
· Inositol lipid (IP3)
Coupled to tyrosine kinase or G protein linked receptors.
IP3 diffuses into the cytoplasm and associates with Ca+ challens in e.r. membrane
· Cyclic adenosine monophosphate (cAMP)
Coupled through G proteins and generate second messenger cAMP, which activates protein kinase A
· JAK/STAT
Protein kinases in the cytosol (Janus kinases - JAK), phosphorylate downstream proteins (signal transducers and activators of transcription - STATs).

Transcription Factors: c-myc, p53, Rb

Cell Cycle Regulation
Cyclins interact with cyclin-dependent kinases (CDKs)
In G2 cyclin B binds CDK1- necessary to enter M phase. After M over, degraded by ubiquitin-proteasome pathway.
p21 and p27: CDK inhibitors
In G1, cyclin D activates CDKs which hyperphorphorylate Rb, disrupting binding to E2F. Released E2F activates transcription of genes required for S entry.
Checkpoints detect problems in DNA replication, DNA repair and chromosome segregation. Activated checkpoints halt the cell cycle. e.g. p53 activated by DNA damage increases expression of p21, CDK inhibitor.

Growth Inhibition
Contact inhibition
TGF-b binds cell-surface receptors with ser/thr kinase activity; inhib progression to S phase.