Lecture 8

Lecture 8 - Lecture #8 Thursday 4/24/08 -1- Annoucements:...

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Lecture #8 – Thursday 4/24/08 - 1 - Annoucements: MIDTERM = MAY 6, TUESDAY (in class) - Midterm . 50 Multiple Choice questions, Scantrons will be provided. You need to bring: #2 pencil and some form of picture identification. No Review Session, so GO TO OFFICE HOURS or email. Cell Cycle - Already talked about in relation to TSGs (i.e. Rb) - Controlled by cyclins (that’s how they were purified). o Associate with CDKs (can’t function in the absence of cyclins). o CDKs are not highly regulated through the cell cycle, but the cyclins are. But CDKs are controlled by the absence/presence of cyclins. The figures in the lecture are from your textbook. Figure 8.3b: Phases of the Cell Cycle G0 G1 S G2 M - There are checkpoints employed in response to DNA damage G1: - Can vary in length (cells can stay in G1, proceed to S or go into G0) and is influenced by extracellular signaling. - Contains the R point (restriction) beyond which the cell is committed to continuing the cell cycle. Figure 8.9 and 8.10: How Cyclins are regulated depends on Rb. Figure 8.19: Rb - Exists in one of three states: o Un-phosphorylated o Hypo-phosphorylated (low levels) o Hyper-phosphorylated (high levels) - Hyper-Phosphorylated state: Rb ceases to interact with/inhibit a series of transcription factors called E2F. o This releases E2F to transcribe genes for late G1 progression. o Ex. Cyclin E (critical for the progression into S phase) - Hyper-phosphorylation via CDKs (specifically CDK 4 and 6) associated with cyclin D drives the expression of other cyclins for the next phase, perpetuating the cycle. o Like a positive feedback loop - There are a number of things in this process that relate to malignancy: o The D type cyclins (there are three: D1, D2 and D3) are very influenced by growth factor signaling o Cyclin D expression is mediated by Immediate Early Genes (ex. AP-1, which is mediated by c-fos and c-jun)
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Lecture #8 – Thursday 4/24/08 - 2 - o c-fos and c-jun are stimulated by GF signaling: GF RTK Ras Raf AP-1 Cyclin D CDK Rb phosphorylation activation of E2F transcription factors Cyclin E and other genes involved in G1/S phase transition. (simplified pathway) - It’s all dependent on RTK levels of activation which, as we’ve discussed before, are prone to malignant mutations. - - So this whole pathway really depends on the Immediate Early Genes (again, already discussed in the context of malignant mutations) - Once the cell is committed to the cell cycle (by passing the R point), nothing short of DNA damage will stop the cell. o Genes that are important in the progression of the cycle (RTKs, RAs, TF – AP1, cyclins – these are all involved in malignant transformations. -
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This note was uploaded on 07/21/2008 for the course BIMM 134 taught by Professor Johnson during the Spring '08 term at UCSD.

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Lecture 8 - Lecture #8 Thursday 4/24/08 -1- Annoucements:...

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