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1) Cell growth and cell division are distinct phenomena a. Cell proliferation requires cell division and growth progress through the cell cycle leads to cell division growth = increase in mass / time cancer cells must proliferate for a tumor to increase in size b. Growth and cell division can be uncoupled during development a neuron grows without cell division early embryos can have cell division without growth yeast cells must grow to a certain sized before passing through START 2) Mammalian cells can be grown in culture a. Tissues, usually from very young organisms, can be dissociated into their component cells for the establishment of cell cultures a defined medium is necessary to support cell division in culture primary cultures are made directly from a tissue cells in primary culture have a finite life span they will divide a certain number of times before senescence This is called the Hayflick limit The Hayflick limit is somehow related to aging cells taken from a 40-year-old stop dividing after about 40 doublings, cells taken from an 80-year-old stop after about 30 doublings when cells reach the Hayflick limit they senesce and eventually die b. Immortilized cell lines can be made from primary cultures a cell can pass through crisis at the Hayflick limit and survive individual cells that pass through crisis give rise to cell lines cell lines and cancer cells are immortal the only immortal cell type in an animal is the germ line 3) Growth factors are necessary for cells to grow in culture a. growth factors induce cell proliferation; i.e. growth and cell division The restriction point is defined as the point of time during G1 that a cell commits to completing a full division cycle even in the absence of growth factor Prior to the restriction point cells enter and exit G0 quiescence depending on nutrient and growth factor availability no growth factor or insufficient nutrients and cells enter G0 b. growth factors induce gene expression early response genes are induced within minutes; e.g. transcription factors-fos and myc delayed response genes are induced within hours; e.g. cyclin D delayed response genes require the expression of early response genes 4) Growth factors induce cyclin D expression a. cyclin D expression is regulated by RAS/MAPK pathways cyclin D binds to cdk4 or cdk6 (which are essentially equivalent) cyclin D transcription and stability is stimulated by growth factors b. cyclin D expression triggers the G1-S transition c. cyclin D/cdk4 may also control growth cyclin D/cdk4 overexpression in flies induces growth ras activation causes growth in flies mutation of the cdk4 inhibitor p18 causes hypertrophy in mice d. cyclin D expression is lost upon removal of growth factors (mitogens) 5) Cyclin D is an oncogene a. inappropriate increases in gene expression can lead to cancer chromosome inversions and translocations change gene expression b. cyclin D gene is involved in chromosome rearrangements found in cancer 1. parathyroid adenomas; parathyroid hormone enhancer drives cycD expression Parathyroid adenomas are benign tumors of the parathyroid glands, which are located in the neck and help to regulate calcium metabolism 2. mantle cell lymphoma; immunoglobin heavy chain enhancer inappropriately drives cycD expression in B lymphocytes characterized by an expansion of the mantle zone of a lymph node can spread to the bone marrow 55-60% of cases have the 11:14 translocation 6) Genetic Instability is a hallmark of cancer cells a. The following properties define genetic instability 1. gene amplification 2. anueploidy: chromosome gain and loss 3. chromosome rearragements; inversions, translocations, and deletions 4. somatic mutations