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62 Cards in this Set
- Front
- Back
Stress-activated kinases
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Inhibit proliferation
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JNK has 10 isoforms as a result of
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Alternative splicing
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JNK binds and phosphorylates p53 leading to
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p53 stabilisation
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JNK activates
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c-Jun
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c-Jun induces the transcription of
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AP-1
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c-Jun can repress
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p53
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p38 induces the transcription of
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IL-1 and TGF-alpha
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p38 is activated by
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cytokines and environmental stress
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JNK is activated by
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DNA damage, decrease in GFs, UV radiation, serum, cytokines
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JNK genes
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1-3
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Most frequent mutations of MAPK in cancer
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Ras and B-Raf
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When ERK is mutated in cancer, genes are amplified e.g.
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AP-1 and c-myc
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Ras and B-raf mutations
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Rarely occur in the same tumour
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Co-expression of Ras and B-Raf leads to
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senescence/lethality
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Ras mutations prevent
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GTP hydrolysis
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Ras associated with the membrane due to
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Isoprenylation at the c-terminus
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Farnesylation inhibitors have been unsuccessful because
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Ras is expressed in all cells
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B-Raf mutations are common in
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Papillary Thyroid and Malignant melanomas
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>90% B-Raf mutations occur at
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V600E
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Ras V600E residue is in the
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activation loop
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In colon at B-Raf mutations often occur along with
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CpG island methylation
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B-raf can heterodimerise with
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Raf-1
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B-raf and Raf-1 heterodimerise when stimulated by
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Mitogens and 14-3-3
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Raf-1 can be suppressed by
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PKA
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Ras mutations uncouple
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PKA and Raf-1
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Mutations rarely occur at
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A-Raf
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Any mutations that occur in A-Raf are
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polymorphisms
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Raf activates
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MEK
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When Raf is the strongest activator?
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B-Raf
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Early gene products of ERK include:
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fos, jun and myc
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sustained ERK signalling promotes
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Cyclin D
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High levels of ERK signalling promotes
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p21
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ERK can promote the transcription of AP-1 by up-regulation of
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Fra-1
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Sorafenib is a non-selective inhibitor of
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Raf
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Raf-chaperone that is the target of inhibition
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HSP90
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Clinical trials target Raf by inhibiting
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MEK1/2
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Difference between c- and v-Jun, v- Jun lacks the...
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delta-domain
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c-Jun delta domain binds to
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JNK and HDAC3
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JNK regulates c-Jun
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transcription
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GSK3 regulates c-Jun
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abundance
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GSK3 phosphorylates c-Jun causing
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Ubiquitination
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High levels of GSK3 usually lead to
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Reduced c-Jun
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The Wnt and P13K both regulate
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GSK3
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Wnt activates dishelleved and Frat leading to inhibition of
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GSK3
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P13K activates
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Akt, leading to inhibition of GSK3
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Gain-of-function mutations in Wnt and P13K lead to
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No degradation of c-Jun
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Before GSK3 can phosphorylate c-Jun
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ERK phosphorylates c-Jun
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v-Jun the Ser423 is mutated so
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ERK does not phosphorylate it
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The best studied immediately early gene is
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Fos
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Modifying chromatin and recruit RNA polII leads to
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Transcription
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Fos is activated by histone (H3S10) acetylation which recruits
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14-3-3 and BRG1
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Contains a constitutively negative charge in the N-region
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B-Raf
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Cancers with high incidence of B-Raf mutations include:
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Papillary thyroid carcinoma and malignant melanoma
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Activating mutations in RET (RTK) are common in
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Papillary thyroid carcinoma
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RTK recruit Grb2 via the
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SH2 domain
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Grb2 recruits Sos via the
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SH3 domain
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Sos activates
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Ras
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PTEN is a
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tumour supressor
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PIP2 -> P1P3 is catalysed by
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P13K
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PIP3 -> PIP2 is catalysed by
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PTEN
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Antisense oligonucleotides are used in treatment to target
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Ras and Raf
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Uses lysine residues to recruit to the membrane (not farnesylation)
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K-Ras
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