Download Senescence and Hayflick Limit

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