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SessionVIICellCycle_II

SessionVIICellCycle_II - Regulation of cell cycle and...

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Regulation of cell cycle and proliferation in stem cells Lecture VIII
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SCs must divide in order to generate progeny cells and fulfill their function http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg
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Major differences among types of stem cells ESCs - as far as we can tell they are immortal, divide indefinitely, rapidly, and continuously (no G0 state of cell cycle) Tissue SC - in vivo -they are largely quiescent - In vitro (in culture or in transplants- they divide but eventually exhaust their potential (senescence)
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Cell cycle http://images2.clinicaltools.com/images/gene/cellcycle.jpg
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Cell cycle regulation Regulated by "Growth Factors" MPF (mitotic promoting factor) * Cdk (cyclin dependent kinase) - a cell division control protein - active only when bound to cyclin * Cyclin - a protein w/ cyclically varying amount - binds to cdk under high concentration MPF switches on/off target cell cycle proteins by phosphorylating them
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http://fig.cox.miami.edu/~cmallery/150/mitosis/sf8x18a.jpg What are the mechanisms behind rapid proliferation and unusual cell cycle structure? CDK4,6 then CDK2 First D (early G1) then E (late G1)
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Rapid proliferation of pluripotent cells in embryonic epiblast 4.5~6.0 dpc (days post coitum) : ~10 h (epiblast expansion, 20~25 660 cells) 6.5~7.0 dpc: ~4.4 h (gastrulation 660 ~4000 cells) Cell cycle structure lacking fully formed G1 and G2 gap phases, giving a high proportion of S-phase (50~60%) Niwa, Development, 2007
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ES cells proliferation in culture Mouse (m)ES cells - behave in many ways like neoplastic cells - Proliferate indefinitely while maintaining pluripotency - No quiescence state, no senescence - Multiply in the absence of serum- not dependent on growth factors - No contact inhibition or anchorage dependence - Tumorigenic when injected into adult mice (teratomas) mESCs are genotypically wild type genetic lesions in growth-controlling protooncogenes and tumor suppressor genes, contrasting all other types of neoplastic cells How is cell cycle regulated?
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Do rapidly cycling mESCs have a similar cell cycle structure to in vivo pluripotent cells? mESCs have a shortened cell cycle due to the truncation of G1 phase Stead et al., Oncogene, 2002
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What are the mechanisms behind rapid proliferation and unusual cell cycle structure? Cdk activity Cdk inhibitors pRb-E2F pathway Ras/ERK signaling pathway PI3 kinase pathway
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What are the mechanisms behind rapid proliferation and unusual cell cycle structure?
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