p53 and Apoptosis: Master Guardian and Executioner Part 2
p14arf in human cells is a antagonist of Mdm2. The expression of ARF causes a rapid increase in p53 levels, so what would you suggest?.. The enemy of an enemy is a friend.. ARF can induce rapid increases in p53 levels because it kidnaps and inhibits p53 s destroyer, Mdm2. in normal, unstressed cells, Mdm2 must be allowed to perform its normal role of keeping p53 levels very low. In many human tumors, inactivation of the p16ink4a/p14arf locus by genetic mutation or epigenetic promoter methylation can be demonstrated
many of the human cancer cells that retain wild-type p53 gene copies have eliminated p53 function by inactivating their two copies of the gene encoding ARF
ARF and p53-mediated apoptosis protect against cancer by monitoring intracellular signaling Several ways to eliminate cells that carry too much E2F activity and, by implication, have lost proper prb control. Huge E2F1 activity drives expression of a number of genes encoding apoptotic proteins. ( caspases 3, 7, 8, and 9), pro-apoptotic Bcl-2 related proteins (Bim, Noxa, PUMA), Apaf-1, and p53 s cousin, p73). The p53-dependent apoptotic program is often triggered by elevated E2F activity. p14arf gene carries an E2F recognition sequence in its promoter. Might be a target only at conditions with high level of E2F
prb E2F ARF Mdm2 p53 apoptosis ARF function is eliminated by a variety of molecular strategies during tumor formation = mutation of the p53 gene. These discussions suggest that E2F-induced apoptosis functions solely as an anticancer mechanism designed to eliminate unwanted, pre-neoplastic cells. other major oncogenic signaling pathway can also contribute significantly to increased ARF expression and thus to p53 activation downstream of Ras.
Hyperactive signaling by Ras or its immediate downstream partners, Raf or B-Raf drives increased ARF expression and, acting via Erk/MAPK, the expression of p53. These cells have to either neutralize p53 function or confront rapid elimination by p53-dependent apoptosis. In a transgenic mouse model of lung adenocarcinoma development, signaling by Ras oncoprotein and its activated downstream effector, phosphorylated Erk/MAPK.
p53 functions as a transcription factor that halts cell cycle advance in response to DNA damage and attempts to aid in the repair process Transcription-activating powers of p53 depend on more than its ability to recognize and bind this sequence within a promoter and acetylation, glycosylation, phosphorylation, and ribosylation. This affects the ability of p53 to interact physically with other factors (ex. phosphorylation of p53 s N-terminal transactivation domain can increase its ability to bind the Taz2 domain of the p300 co-activator). P300 then contributes to transcriptional activation by acetylating nearby histones H3and H4 as well as p53 itself.
What is the level of Mdm2 in cancer cells with mutant p53? Similar when cancer cells infected with SV40 LT, then p53 will stay high. What a bout its half life will be
p53 suppresses cancer through transcriptional activation, by regulating diverse biological processes through transactivation of target genes.
p53 suppresses cancer through transcriptional activation, by regulating diverse biological processes through transactivation of target genes. P53 works vis p21cip1 which is able to inhibit two CDKs CDK2 and CDC2 that are active in the late G1, S, G2, and M phases of the cell cycle. if the chromosomal DNA of a cell should suffer some damage during the G1 phase of the cell cycle, p53 will become activated, both by rapid increases in its concentration and by post-translational modifications that enable it to function effectively as a transcription factor. p53 will then induce p21cip1 synthesis, and p21cip1, in turn, will halt further cell proliferation
But this is not every thing! DNA repair proteins are mobilized far more effectively in cells carrying wild-type p53 alleles than in those with mutant p53 alleles. DNA polymerase β, is more active in p53 cells. p21cip1 induced by p53 can engage the DNA polymerase machinery at the replication fork and halt its further advance down DNA template molecules. In the event that the DNA is successfully repaired, the signals that have protected p53 from destruction will disappear. p21cip1 mediates some, but not all, of the tumor-suppressing activities of p53.
p53 often ushers in the apoptotic death program In response to massive, essentially irreparable genomic damage p53 will trigger apoptosis.
p53 inactivation provides advantage to incipient cancer cells at a number of steps in tumor progression Bcl-2 blocks apoptosis, while p53 promotes it. Bad can be phosphorylated by Akt/PKB, which decreases Bad s ability to hold the mitochondrial channels in an open configuration; this explains some of the anti-apoptotic effect of the Akt/PKB kinase. Bax and Bak proteins congregate at the outer surface of the mitochondrion, where they participate, in ways that are still
Altogether, the human genome is known to encode twenty-four Bcl-2 related proteins; six of these are antiapoptotic, while the remaining eighteen are pro-apoptotic.
- Bim is regulated at the transcriptional level and post-translationally via phosphorylation by Erk, which results in its ubiquitylation and degradation. - Bid is liberated from its inhibitory domain by caspases which are activated by granzyme b
Cancer cells invent numerous ways to inactivate some or all of the apoptotic machinery Toward neoplasia cells face many stressors, all of them are dangerous! Anoxia, deregulation of the prb pathway, activation of oncogenes like myc and ras, and various forms of DNA damage. Therefore cancer cells inactivate apoptosis via several ways. The p53 gene is altered in almost half of all human cancer cell genomes. Some times p53 is mislocalized. In many, ARF is no longer expressed by deletion of the ARFencoding gene or by promoter methylation Most sarcomas overexpress Mdm2. Some cancer cells deploy a protein termed FLIP
Many melanoma cells exhibit methylation promoter of the APAF1 gene. The pro-apoptotic Bax gene is inactivated by mutation in more than half the colon cancers. BCL2 expression is found to be elevated in more than half of human tumors. Hyper activation of the PI3K Akt/PKB pathway. Once Akt/PKB becomes activated by the PIP3 that accumulates, it can phosphorylate and thereby inhibit pro- poptotic proteins such as Bad, caspase 9, and IκB, and at the same time phosphorylate and activate Mdm2, the key antagonist of p53 Expression activation of the NF-κB transcription factor and therfore IAP-1, IAP-2, XIAP, IEX-1L, TRAF-1, and TRAF-2, which serve to block both the intrinsic and extrinsic apoptotic programs.
In activation of apoptotic machinery in cancer cells
In activation of apoptotic machinery in cancer cells
In activation of apoptotic machinery in cancer cells