cell determination and cell sequence Flashcards
Mechanisms for memory and the two ways
Once a cell differentiates it remembers this state even without any external inducing signal
Two ways are chromatin remodeling and positive feedback
Positive feedback
Signal only affects A and is only required to start cycle between A and B
A and B can resume the cycle without signal
Melanocyte differentiation
MITF is the master gene regulator for melanocytes
When homozygous, the MITF gene causes loss of all melanocytes Eyes become small due to loss of pigmented retina
In genetics
+ means a normal gene
- means a mutant gene so -/- both copies mutant
Waadenburg syndrome 2 (causes)
Deafness (due to loss of pigment in ears)
Congenital patchy loss of pigment in skin
MC1R-cAMP signalling in melanocytes
MSH binds to MC1R on the membrane
This activates Ad cyclase enzyme that form PKA which are cAMP-dependent CREB proteins are phosphorylated and activated by PKA These PCREB enter the nucleus and bind to CRE in gene promoter This increases MITF in melanocytes via transcription
Activating melanocyte-specific genes
MITF is transcribed and translated
Produces a MITF protein MITF acts as a transcription factor for transcription or MC1R Speicialised proteins are made
Melanocyte differentiation can be switched on by MSH and stabilized even without it
Skeletal muscle
Myogenic factors – master gene regulators in skeletal muscle differentiation. Can bind to DNA and E proteins
E proteins: widely expressed transcription factors ID1: a protein in myoblasts. They strongly bind to E proteins but not DNA
Cell senescence
Major defense against cancer
Strongly implicated in symptons of ageing Permanent cell growth arrest after extended cell proliferation Cell lifespan: The total number of cell doublings a cell goes thorough before senescence When cells go into senescence sometimes they have biological markers: Many more lysosomes in comparison to normal cells Protein p16 a cell cycle inhibitor
Telomeres
Hexamer sequence TTAGGG repeated thousands of times at the end of the chromosome
3’ ends of DNA not replicated normally because RNA primer has to bind beyond the part to be replicated So enzyme telomerase is needed to maintain the length of the telomere
Telomerase
Protein-RNA complex
Replicates telomeric DNA Reverse transcribing DNA from its own RNA In normal somatic cells there’s no TERT, so telomeres shorten as cell divides Replicative senescence is triggered by telomeres getting to a particular short length Germline cells are immortal as they have TERT so telomeres remain long – the cells can divide forever Approx. 90% of cancer cells have TERT so divide uncontrollably (immortal)
Effector pathway of cell senescence
Telomere shortening switches on DNA damage signalling
This turns on p53 and then p21 (growth inhibitor) This inhibits CDK1/2 resulting in an arrest in cell division Radiation, oxidative stress, DNA damage P16 switched on which inhibits CDK4/6 RB is activated which inhibits E2F resulting in an arrest in cell division
Cancer cell abnormalities
Expression of TERT
P53 defects P16 defects
Effect on ageing
Evidence is accumulating that cell senescence is also behind many of the symptons of normal ageing:
Telomere length (measured in blood cells), variable, but on average falls with age. Typically very short in people aged >100. P16 and other senescence-associated proteins are expressed increasingly in ageing tissues. Telomere length at birth varies between people: genetically linked to age at death. Defective genes for telomerase subunits give syndromes with premature ageing and early death. P16 (CDKN2A) locus also genetically associated with human senile defects – cardiovascular disease, frailty, type II diabetes, neurodegeneration, and cancer.
Embryonic stem cells
Express TERT
Naturally immortal Totipotent though sometimes called pluripotent
