What do inducers cause cells to do

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Z Naturforsch C. Caffeic acid phenethyl ester protects against oxidative stress and dampens inflammation via heme oxygenase 1. Int J Oral Sci. Another well-characterised transcriptional target of TP53 is Zmat3 96 that has a poorly defined function but has been shown to impact on the response of cells to apoptotic stimuli.

This may well be pertinent to tumour development and cancer therapy. Although the role of p53 and p63 in the induction of apoptosis is widely accepted, there are also reports that p53 can regulate additional non-apoptotic cell death pathways.

For example, p53 was reported to open the mitochondrial permeability transition pore to thereby induce necrotic cell death. For example, p53 activation by nutlin-3a results in apoptosis in some cells but cell cycle arrest and senescence in others both malignant and nontransformed. For example, cells within the gastrointestinal tract and the haematopoietic system 54 , 55 , 91 are particularly vulnerable to pinduced apoptosis that underlies their prominent involvement in toxicity associated with DNA damage-inducing chemotherapy.

We can speculate on factors that may differentiate the p53 response: post-translational modifications on the p53 protein e. These are all fascinating possibilities that require much further investigation. The finding that p53 can induce apoptosis led to the widely accepted assumption that out of all the cellular effector processes activated by p53 Figure 3 this is the most critical, possibly even the sole, process by which p53 suppresses tumour development reviewed in Vousden and Lane 9.

This made sense: after all, if cells during the early stages of neoplastic transformation are killed through pinduced apoptosis, no fully transformed malignant cells will emerge from this clone. However, matters are not that simple. The CDK inhibitor p21 is essential for cell cycle arrest and also a major contributor to cellular senescence.

Moreover, combined loss of PUMA and p21 or mutations in the two transactivation domains of p53 that are critical for the transcriptional induction of Puma , Noxa and p21 accelerate c-MYC-driven lymphoma development and mutant RAS-driven lung cancer development to a much lesser extent than loss of p53 Figure 4. The relative importance of the induction of apoptosis to overall TPmediated tumour suppression is likely to vary depending on the type of cell undergoing neoplastic transformation and the nature of the oncogenic lesions that drive tumorigenesis.

P53 activates a multitude of cellular effector processes. Model showing a selected cellular effector processes that can be activated by p Some, but not all, of the p53 target genes that are critical for the execution of these processes are indicated. The challenge remains to understand of which of these processes are critical for tumour suppression in which setting; that is, cell of origin undergoing neoplastic transformation and nature of the oncogenic lesions driving their transformation.

Impact of pinduced apoptosis on tumour development. Important insight into the mechanisms that are critical for TPmediated tumour suppression also came from experiments using an elegant genetically engineered mouse model in which p53 activity can be turned on or off at will.

Instead, p53 function was required during the later recovery phase. The very rapid proliferation of progenitor cells bearing oncogenic lesions, which is likely to also be the basis of the development of many other cancers, may facilitate the acquisition of mutations in oncogenes or suppressor genes that further drive neoplastic transformation. Some initially paradoxical findings are consistent with this. The p53 is unusual among tumour suppressors.

In tumours that are driven by mutations in the tumour suppressors PTEN or RB, the expression of these proteins is usually lost completely because of the nature of the mutations selected for during tumorigenesis reviewed in Knudsen and Knudsen and Yin and Shen In contrast, many tumours that are driven by mutations in TP53 express high levels of the mutant p53 protein and show a loss of the other allele of TP53 reviewed in Vousden and Lane 9 and Freed-Pastor and Prives In fact, the high-level mutant p53 protein expression can be used as a diagnostic marker for cancers driven by mutations in the TP53 gene reviewed in Liu and Gelmann The highly expressed mutant p53 protein can promote tumorigenesis in three ways: 1 loss of the WT p53 activity, 2 DNEs over the WT p53 protein early in transformation before loss of the WT TP53 allele, through the formation of mixed tetramers containing both wild-type and mutant p53 proteins and 3 de novo GOFs that are mediated through interactions of mutant p53 protein with other transcription factors and tumour suppressors e.

As early in transformation, mutant p53 levels are often variable and low, it appears likely that the GOF effects may only come into play at a late stage of transformation. It is obvious how loss of the WT p53 function contributes to the tumour promoting action of mutant p53 but the mechanisms by which the DNE and GOF effects of mutant p53 drive tumour development are not established.

A detailed understanding of the role of these processes in the development as well as the sustained growth of tumours is anticipated to identify targetable vulnerabilities for the development of novel cancer therapies. Impact of mutant p53 proteins on tumour development. Model depicting the mechanisms by which mutant p53 proteins, which are frequently highly overexpressed compared with the wild-type p53 protein , on tumour development.

In conclusion, TP53 is arguably one of the most important if not the most important genes in human cancer. It appears that p53 is critical for tumour suppression not during the acute response to cellular stress, such as DNA damage e.

The p53 transcription factor activates several effector processes, apoptotic cell death being one of them. Thus, additional cellular processes, either by themselves or in a manner overlapping with the aforementioned mechanisms, must account for the potent tumour suppressive action of p Identifying these signalling pathways and how they are integrated will provide exciting research opportunities for several years.

A better understanding of pmediated apoptosis and pmediated tumour suppression more generally holds promise for various potential clinical applications. These include improving the efficacy of anticancer therapies that rely on p53 activation, reducing the toxicities associated with chemotherapy and radiotherapy and improving haematopoietic stem cell transplant conditioning regimens and perhaps also in nonmalignant settings where abnormal induction of cell death pathways that may in part be driven by p53 contributes to tissue damage, such as myocardial infarction and cerebral ischaemia.

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Transcriptional regulation by p one protein, many possibilities. Cell Death Differ ; 13 : — The expanding universe of p53 targets. Nat Rev Cancer ; 9 : — Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Abbas T, Dutta A. Sengupta S, Harris CC. Nat Rev Mol Cell Biol ; 6 : 44— Michael D, Oren M. The p53 and Mdm2 families in cancer. Curr Opin Genetics Dev ; 12 : 53— Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p Rescue of embryonic lethality in Mdm2-deficient mice by absence of p Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin Since each base pair in the E.

This is much greater than the concentration of repressor or Cro, and can be treated as a constant. This can be expressed as the fraction of total repressor molecules as follows:. This means that only 1.

Even though the affinity of l repressor for its operator or for nonspecific DNA is less than seen for the lac repressor, and the amount of l repressor is about 10 times higher, the l repressor is still distributed between specific and nonspecific sites.

Very little is not bound to DNA. The relevant reaction is. The specificity, which is the ratio of Ks,r to Kns,r can be used to calculate the ratio of free to bound operator. The relevant equations are. Using the equation for specificity as in 4. Dividing eqn 2 by eqn 5, you obtain. As calculated in 4. Thus the. The distribution of l repressor and Cro to nonspecific sites was used in this treatment to calculate the same low concentration for free repressor and Cro problem 4.

The cooperativity at the operator sites means that less repressor is needed to fill the sites. The sigmoidal shape of the binding curve for cooperative interactons also means that a smaller decrease in [R] will lead to dissociation of repressor from a greater fraction of operators, giving a more dramatic response to a lowering of [R].

There is no nut site in this transcript, hence transcription from p int is not susceptible to N-mediated antitermination. Thus the transcript terminates at t int and the secondary structures that target RNases to a transcript are not formed. Thus the int transcript is stable, and Int protein is made during lysogeny. The ribosome will progress to the trp codons in the leader and either stall low trp or continue to a termination codon high trp.

Stalling of the ribosome at trp codons A situation prevents formation of the termination loop between regions 3 and 4 of the mRNA. Progress to the UGA terminator allows the loop to form B situation and thus terminate transcription.

Attenuation depends on the tight coupling between transcription and translation in bacteria. In order to understand how regulatory mechanisms work, it's first necessary to understand that not all nucleotide sequences in a strand of DNA code for the production of proteins.

Rather, some of these noncoding sequences serve as binding sites for the various protein molecules required to start or regulate the transcription process. For example, a group of nucleotides known as a promoter sequence lies near the beginning of most genes and provides a binding site for RNA polymerase to begin transcription. Similarly, other noncoding sequences near the promoter sequence function as protein binding sites that can either induce or block transcription. This basic system affects gene expression in both prokaryotes and eukaryotes, albeit in different ways.

One especially well-known operon is the lac operon found in E. This operon contains the three genes E. Lactose is a sugar molecule that these cells often use as a source of energy. When lactose is not present in a bacterium's environment, the protein products of these three genes aren't needed. As a result, a repressor protein binds to the operator of the lac operon and blocks transcription of the three genes.

In contrast, when lactose is present, a molecule of this sugar binds to the repressor protein and changes its shape. The shape change prevents the repressor from binding to the operator, thereby permitting transcription of the three genes in the lac operon to occur.

In this case, lactose itself "turns on" the genes of the lac operon, which means that it acts as an inducer.

In prokaryotes, a similar system can also be used to turn genes off. Consider, for example, the E. This operon functions much like the lac operon except for one major difference — specifically, the repressor protein in this system only binds with the operator sequence when tryptophan is present.

Here, tryptophan binds with the repressor, thereby changing the repressor's shape such that it fits with the operator. This means that tryptophan acts as a co-repressor, because it helps turn the genes of the trp operon off. Gene expression is much more complicated in eukaryotic cells than it is in prokaryotic cells. This is due, in large part, to the fact that eukaryotic cells must differentiate into different cell types, and they also contain a greater number of genes than prokaryotic cells.

Furthermore, the transcription and translation sites of eukaryotic DNA are separated from one another by the nuclear membrane. Given these complicating factors, eukaryotic cells employ a greater variety of control strategies than prokaryotic cells, and they do so at various steps in both transcription and translation.

Nonetheless, each of these strategies begins at the level of DNA. In eukaryotes, control at the level of transcription is specific and efficient.