p53 - Wikipedia
by which p53 induction mediates cell cycle arrest. p21CIP1 inhibits kinase activity of To reexamine p53 function in cell cycle control we have studied cell cycle Because these cell lines do not undergo apoptosis upon p53 overexpression . To assess more precisely the relationship between an initial G 1 arrest and a. pmediated cell death: relationship to cell cycle control Recently, wt p53 elucidate the biological activities of wt p53, whose loss has also been found to. pMediated cell death: Relationship to cell cycle control these cells undergo rapid cell death upon induction of wild-type (wt) p53 activity at.
Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.
A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other.
In this case, p53 can initiate events leading to tanning.
p53-mediated cell death: relationship to cell cycle control.
The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein. Stem cells Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. Embryonic stem cells p53 is maintained at low inactive levels in human embryonic stem cells hESCs. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1.
This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation.
Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency than normal cells. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders. This activation is marked by two major events.
First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain.
Like in many other cases in which apoptosis has p Alternatively, TGF-1 may modulate directly the bio- been shown to take place 1, 61here too DNA fragmenta- chemical properties of the p53 protein itself. Either way, the tion precedes formal cell death by several hours. One could argue that in particular cell types, apoptosis Rapid c-myc mRNA reduction precedes pmediated cell occurs by default whenever a G1 arrest is imposed.
A growing number of reports now suggest that p53 expression of wt p53 can often elicit an arrest in G1 11, possesses transcription regulatory activities 13, 14, 17, 31, In most cases studied thus far, this arrest is 46, 47, 53, 64, 66, It was therefore of interest to reversible and is not followed by a significant loss of viabil- determine whether wt p53 activation had any measurable ity.
However, in cells in which growth arrest is coupled with effects on the levels of specific transcripts. One obvious apoptosis, wt p53 activity could be expected to lead to cell candidate was c-myc. A close correlation has been shown to death as an obligatory sequel of the block in cell prolifera- exist in Ml cells between the biological activities of IL-6 and tion.
This is clearly not the case in the transfected Ml cells. Steady- Under the influence of wt p53 activity, these cells continued state levels of c-myc mRNA were therefore monitored in to move through the cell cycle even as the chromosomal LTR-6 cells after exposure to wt p53 activity.
It was found DNA was being fragmented. This indicates that p53 can Fig.
Hence, repression of c-myc expression is an early Ml cells does not necessarily imply that the control of cell event in this apoptotic paradigm. Interestingly, the presence survival is totally unlinked to the cell cycle. In fact, our data of IL-6 appeared to delay partially the reduction in c-myc suggest that cells may have to reach G1 in order to become mRNA levels.
It is noteworthy that IL-6 alone actually also committed to pdependent death. Critical targets for p53 may thus be present specifically in G1. Whereas in certain causes a marked drop in c-myc mRNA, but with much cases the interaction between wt p53 and such targets may slower kinetics than does wt p53 25, Our data suggest that, in Ml due to a general transcriptional repression.
Thus, no com- cells, the commitment to cell death takes place preferentially parable reduction was found when steady-state levels of in G1. The final stages of the process apparently occur later, c-jun mRNA were determined data not showneven most probably during the S phase. This timing may imply though the c-jun promoter has been shown to be down- that once sufficient DNA cleavage has occurred, cells enter- regulated by overexpressed wt p53 in fibroblasts Simi- ing S cannot successfully exit it.
It is of note that apoptotic larly, there was no reduction in histone Hi0 mRNA, at least cell death in S phase has been described before Thus, the activation of wt p53 in Ml cells Recent data suggest that p53 acts as a transcriptional mod- appears to lead to a selective repression of c-myc expres- ulator, upregulating the expression of some genes while sion.
Additional genes, yet to be identified, may also be repressing that of many others 13, 14, 17, 31, 46, 47, 53, 64, similarly down-regulated. Positive regulation may rely on the ability of p53 to VOL. Sachs for stimulating discussions, by wt p53, but not by mutants of the various types found in Interpharm, Inc. Humanities and The Minerva Foundation Munich. Collaborative molecular circuitry poised to execute the apoptotic process.
The suggestion that p53 is involved in regulating and role in pathology. Whatever the mechanism, Cleveland. Constitutive c-myc expression in an IL dependent myeloid cell line suppresses cell cycle arrest and if wt p53 is indeed necessary for allowing particular cells to accelerates apoptosis.
Willson, and illegitimate survival of such cells, thereby promoting neopla- B. Suppression of human colorectal carcinoma sia. It is possible that the link between wt p53 activity and cell 4.
pmediated cell death: relationship to cell cycle control | Elisheva Yonish-rouach - corrosion-corrintel.info
It has been suggested Ng, and I. Induction of the TRPM-2 gene in that apoptosis may serve as a means for "executing" cells in cells undergoing programmed death. Caron de Fromentel, C. TP53 tumor cells may be subjected to conflicting signals, especially when suppressor gene: This Genes Chromosomes Cancer 4: Growth suppression of human breast cancer pathways. Recent evidence strongly indicates that such cells by the introduction of a wild-type p53 gene. Oncogene imbalance may indeed trigger apoptosis, as seen when cells 6: These cells may harbor one or more activated oncogenes Apoptosis and programmed cell death in immunity.
It appears, however, rather A connection between p53 and apoptosis may also be Vogelstein, and maintaining the stability of the genome 30, 33, It is tempting to speculate that wt p53 may Induction of apoptosis in fibroblasts by c-myc protein.
Prywes, and Our findings do not prove that p53 normally plays a role in C. Wild-type p53 activates transcription in vitro. Nevertheless, several recent findings are Nature London Hence, in both involuting Presence of a potent transcrip- tion activating sequence in the p53 protein.
A transcriptionally active DNA-binding site for tion, in normal human myeloid blasts the resident wt p53 was human p53 protein complexes. Protein synthesis required gests that the ongoing proliferation and survival of such cells to anchor a mutant p53 protein which is temperature-sensitive in vivo require that p53 be kept in an inactive state. Hence, for nuclear transport. Wild- the fact that wt p53 renders myeloid Ml cells IL-6 dependent type p53 can down-modulate the activity of various promoters.
Cell death Human p53 and CDC2Hs genes combine to inhibit the prolifer- mechanisms and the immune system. Induc- of mRNAs associated with programmed cell death in immature tion of bcl-2 expression by Epstein-Barr virus latent membrane thymocytes. Social controls on cell survival and cell death. Bcl-2 is an inner mitochondrial mem- Analysis of p53 mutants for transcriptional activation. BCL2 protein is topographically restricted in anti-oncogene.
Deregulated c-myc expres- Sci. Sup- cell cycle arrest but not other inhibitory responses in Ml pression of c-myc and c-myb is tightly linked to terminal myeloblastic cells. Interferons and interleukin 6 suppress phosphorylation of the The Autocrine ,B-related interferon controls c-myc suppression and polypeptide encoded by the cDNA for human cell surface growth arrest during hematopoietic cell differentiation.
Cell antigen Fas can mediate apoptosis. Interleukin-6 is Bruno, Z. Constitutive a permissive factor for monocytic colony formation by human expression of p53 protein in enriched normal human marrow hematopoietic progenitor cells.
The control of growth and differentiation in R. Participation of p53 protein in the cellular normal and leukemic blood cells.Programmed Cell Death (apoptosis)
Ravindranath, and susceptibility gene products. Levels of p53 protein increase with matura- Deregulated c-myb disrupts interleukin-6 or leuke- K. Selected References These references are in PubMed. This may not be the complete list of references from this article. Int Rev Exp Pathol.
Constitutive c-myc expression in an ILdependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Suppression of human colorectal carcinoma cell growth by wild-type p Induction of the TRPM-2 gene in cells undergoing programmed death. TP53 tumor suppressor gene: Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene.
Genetic mechanisms of tumor suppression by the human p53 gene. Apoptosis and programmed cell death in immunity. Hormone-regulated apoptosis results from reentry of differentiated prostate cells onto a defective cell cycle.
The S-phase cytotoxicity of camptothecin. Induction of apoptosis in fibroblasts by c-myc protein. Wild-type p53 activates transcription in vitro. Presence of a potent transcription activating sequence in the p53 protein.
A transcriptionally active DNA-binding site for human p53 protein complexes. Protein synthesis required to anchor a mutant p53 protein which is temperature-sensitive for nuclear transport.
Wild-type p53 can down-modulate the activity of various promoters. Protein-binding elements in the promoter region of the mouse p53 gene. Cell death mechanisms and the immune system.