21 and 23 March, 2005

Chapter 15

Regulation of Cell Number: Normal and Cancer Cells

Regulated and unregulated cell proliferation

Overview• In higher eukaryotes, cell survival and proliferation are highly regulated

by integrated controls that continually evaluate the state of the cell and its environment.

• Normal cell proliferation is modulated by regulation of the cell cycle.

• Apoptosis eliminates damaged cells and cells needed only temporarily during development.

• The accumulation of mutations in cancer cells allows them to escape apoptosis and proliferation controls.

Cell cycle regulation• Cell cycle phases

– G1: period between mitosis and S– S: period of DNA replication– G2: period between S and mitosis– M: mitosis

• Cyclin– transcribed in specific phase of cell cycle– unstable, resulting in transient activity

• Cyclin-dependent protein kinase (CDK)– substrate specificity and phosphorylation activity

controlled by bound cyclin– phosphorylate serine or threonine of target protein

• Sequential activation of different CDK-cyclin complexes controls cell cycle progression

Apoptosis• Sometimes referred to as programmed cell death• Triggered by variety of signals• Sequential destruction of cell

– fragmentation of chromosomes– organelle disruption– fragmentation of cell

• Driven by activity of caspases– cysteine-containing aspartate-specific proteases– normally inactive as zymogen (harmless to cell)– zymogen form activated by proteolysis– active caspases target other proteins for destruction

Cell-cell communication• Signal-receptor systems• Signal molecules (ligands)

– bind to receptor causing allosteric change– endocrine signals: ligands secreted into

circulatory system– paracrine signals: secreted ligands act locally

• Receptors– usually membrane-bound– conformational change upon binding of ligand

transduces signal to cytoplasm, activating enzyme or enzyme cascade

Extracellular signals

• Cell cycle positive signals: mitogens (growth factors) secreted by paracrine source

• Cell cycle negative controls: ligands initiate signal cascade that inhibits cell cycle progression

• Apoptosis positive controls: signal from neighboring cell

• Apoptosis negative controls: survival factors

Cancer

• Aberrant cell cycle control

• Results from accumulation of mutations in somatic cell clone

• Differ in many ways from neighboring cells

• Genetic basis for all cancer cells– most carcinogens are also mutagenic– some highly penetrant inherited cancer genes– many less penetrant susceptibility genes– oncogenes transmitted by tumor viruses

Mutations in cancer cells• Two categories

– Oncogenes, typically dominant– Mutated tumor-suppressor genes, typically

recessive

• Sometimes associated with chromosomal abnormalities, e.g., translocation that brings gene under control of another gene’s strong enhancer

• Cells that loose ability to undergo apoptosis have longer time to accumulate proliferation-promoting mutations

Tumor-suppressor genes• May encode either negative regulators of cell

cycle or positive regulators of apoptosis• Retinoblastoma caused by mutated RB gene• p53 (refers to protein with mass of 53 kDa)

– ~50% of all tumors have mutated form– normal p53 is transcription factor that is activated

in response to DNA damage• prevents cell cycle progression to allow repair• causes severely damaged cell to undergo apoptosis

– mutated form eliminates apoptotic response, allowing damaged cells to survive, elevating mutation level

Cancer complexities

•Different cancers have different phenotypes with respect to rate of proliferation, ability to metastasize, etc.

•Differences caused by:–differences in somatic cell progenitor–differences in types and severity of mutations

•Research from wide variety of areas applicable to search for cures

Assignment: Concept map, Solved Problem, All Basic and Challenging Problems.