What gene activates p53?
The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.
On DNA damage, p53 is phosphorylated by DNA-PK and RPA is phosphorylated by both ATM at ATR at two sites. Only together can these phosphorylation events disrupt the p53-RPA interaction, liberating both proteins to carry out their DNA-damage-associated functions.
p53 is regulated by an array of posttranslational modifications both during normal homeostasis and in stress-induced responses. More than 36 different amino acids within p53 have been shown to be modified in various biochemical and cell culture studies (Figure 1) (Kruse and Gu, 2008b).
The major mechanism for control of p53 stabilization and activation is dependent on its interaction with and ubiquitination by MDM2 prior to degradation by the proteasome. However, as outlined in Figure 6, multiple proteins contribute to the stabilization of p53 in response to different stress stimuli.
The structural studies and work on short peptides discussed above have clearly demonstrated that mutant p53 proteins can be reactivated with regard to both DNA binding, transcriptional transactivation and induction of apoptosis in human tumor cells.
p53 was restored with the addition of Tamoxifen and in contrast to p53-null tumors that regressed in the two studies described above, lymphomas and sarcomas in this case showed tumor stasis but not tumor regression (Table 1).
Low oxygen concentration, DNA damage, Chemotherapeutic agents, as well as other stress can activate p53. In turn, p53 activates genes that stop cell growth or even trigger the cell to die.
P53, for instance, affects the response of cells to growth factors and growth factor-withdrawal. Furthermore, p53 is involved in the expression of several growth factor- and growth factor receptor genes.
Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis.
The transcription factor p53 is a master tumor suppressor that controls the cellular response to genotoxic stress. Following DNA damage, p53 is activated by phosphorylation at multiple sites in the intrinsically disordered N-terminal transactivation domain.
Does ATM activate p53?
ATM phosphorylates several proteins involved in the DNA-damage response, including p53. We have examined the mechanism by which ATM regulates p53's transcriptional activity. Here, we demonstrate that reintroduction of ATM into AT cells restores the activation of p53 by the radio-mimetic agent bleomycin.
P53 induces apoptosis in nontransformed cells mostly by direct transcriptional activation of the pro-apoptotic BH3-only proteins PUMA and (to a lesser extent) NOXA. Combined loss of the p53 effectors of apoptosis (PUMA plus NOXA) and cell cycle arrest/cell senescence (p21) does not cause spontaneous tumour development.
P53 is tightly regulated by MDM2. Under normal conditions, MDM2 negatively regulates p53 by promoting p53 ubiquitination and degradation via the 26S proteasomal pathway and by blocking its TA activity. However, during genotoxic stress, MDM2 switches to become a positive regulator of p53.
Cell-cycle arrest and apoptosis are the most prominent outcomes of p53 activation. Many studies showed that p53 cell-cycle and apoptosis functions are important for preventing tumor development. p53 also regulates many cellular processes including metabolism, antioxidant response, and DNA repair.
More than 50% of all cancers contain a mutation in the p53 gene. The protein made from this gene is critical for ridding the body of cells that have developed genetic mistakes that could lead to cancer. When it stops working, precancerous cells can slip by and a tumor may develop.
On the DNA level, mutations in TP53 allele could be reversed back to wild-type ones using CRISPR/Cas9 mediated genome editing. One the mRNA levels, mutp53 mRNA could be silenced by RNAi. On the protein level, mutp53 could be reactivated or trageted for degradation by both small molecule compounds and small peptides.
MDM2 then inhibits the p53-mediated transcription of MDM2 and other downstream target genes by binding to p53, blocking its transactivation domain. Through E3 ubiquitin ligase activity, MDM2 promotes ubiquitination of p53, leading to increased p53 degradation.
A TP53 mutation can be inherited from your parents, or acquired later in life from the environment or from a mistake that happens in your body during cell division. An inherited TP53 mutation is known as Li-Fraumeni syndrome.
The TP53 is a gene that instructs the cell to produce tumor protein (p53) ; a vital transcription factor and tumor suppressor. P53 is known as the “guardian of the genome” as it helps in regulating the cell cycle and acts as a tumor suppressor.
Positive staining of p53 was observed in 88 (59.5%) tumors. Tumors with positive p53 staining showed malignant features compared to negative tumors. Mutation of TP53 gene was observed in 29 (19.6%) tumors with higher age and differentiated type.
What does the APC gene do?
The APC protein acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way. It helps control how often a cell divides, how it attaches to other cells within a tissue, and whether a cell moves within or away from a tissue.
P53 induces apoptosis in nontransformed cells mostly by direct transcriptional activation of the pro-apoptotic BH3-only proteins PUMA and (to a lesser extent) NOXA. Combined loss of the p53 effectors of apoptosis (PUMA plus NOXA) and cell cycle arrest/cell senescence (p21) does not cause spontaneous tumour development.
The retinoblastoma (RB) gene is the prototype tumor suppressor gene. It encodes a nuclear protein that acts as a cell cycle control checkpoint at the G1 phase.
The SRY gene provides instructions for making a protein called the sex-determining region Y protein. This protein is involved in male-typical sex development, which usually follows a certain pattern based on an individual's chromosomes. People usually have 46 chromosomes in each cell.