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视频: P53是如何避免癌症发生的p53 protects us from getting cancer!
2013年12月26日 科学知识 暂无评论 ⁄ 被围观 3,177+


p53

p53为肿瘤抑制蛋白(也称为p53蛋白或p53肿瘤蛋白),属于最早发现的肿瘤抑制基因(或抑癌基因)之一。 p53蛋白能调节细胞周期和避免细胞癌变发生。 因此,p53蛋白被称为基因组守护者。 总而言之,其角色为保持基因组的稳定性,避免突变发生。 p53蛋白的分子量于SDS凝胶电泳(十二烷基硫酸钠聚丙烯酰胺凝胶电泳)中测得约为五万三千道尔顿,但依据氨基酸残基计算,p53蛋白的分子量应为四万三千七百道尔顿,两者所测得之分子量差别导因于蛋白质中大量的脯胺酸残基,减缓其在SDS胶电泳中的迁移速度。而此迁移速度减缓的效应在跨物种的p53蛋白皆已被观察,如人类,啮齿动物,青蛙和鱼类。

p53蛋白在避免癌症发生机制上扮演重要的角色,例如,细胞凋亡 (apoptosis) 、基因组稳定性 (genetic stability) 、抑制血管新生 (angiogenesis)。 p53蛋白通过下列之机构达成避免癌症发生:
当DNA受损时,p53蛋白能活化DNA修复蛋白 (DNA repair proteins)。
p53蛋白能抑制细胞生长周期停留于G1/S的节律点上,以达成DNA损坏辨识。 (若能将细胞于此节律点上停留够久,DNA修护蛋白将有更充裕的时间修复DNA损坏部位,并继续细胞的生长周期。)
若细胞的DNA受损已不能修复,p53蛋白能起始细胞凋亡程序,避免拥有不正常遗传资讯的细胞继续分裂生长。
活化的p53蛋白能接合于DNA,促使多个基因表现,包括基因WAF1/CIP1,其为p21蛋白之编码基因。 p21 (WAF1)接合于G1-S/CDK (CDK2) 和S/CDK复合体 (此蛋白在G1/S细胞周期节律点上有重要功能) 以抑制该复合体的活性。 当p21蛋白 (WAF1) 与CDK2形成复合体时,细胞将无法进入到细胞分裂的阶段。 而突变后的p53蛋白将可能丧失与DNA形成有效结合的能力,造成p21蛋白将无法形成,以发出停止细胞分裂的信号。 因此,受损细胞将不受控制的进行细胞分裂,最终形成肿瘤。 根据最近的研究,p53蛋白与RB1程序经由p14ARF蛋白相互调节的可能性更加提高。

p53蛋白借由许多不同的压力形式而激发其活性,其中包括但不仅仅局限于DNA损伤 (包括 UV, IR或化学物质如过氧化氢 (hydrogen peroxide)所造成的损伤),氧化压力 (oxidative stress),渗透压力 (osmotic stress),核糖核苷酸缺乏 (nucleotide depletion) 和丧失调节癌基因表现能力。这些活性激发可由两个主要的事件得出。首先,在受到压力的细胞中,p53蛋白的半衰期 (half-life) 会突然的增加,造成p53蛋白在细胞中的累积。再来则是构型变化 (conformational change) 使得p53蛋白被激发成为转录调节因子 (transcription regulator)。

If DNA gets damaged, more p53 is synthesized, roughly DNA is better repaired. Here are shown roles that p53 plays in the cell to protect the genome of the organism. Video Reference: http://www.learner.org

p53 also known as cellular tumor antigen p53 or phosphoprotein p53 or tumor suppressor p53 is a protein that in humans is encoded by the TP53 gene. The p53 protein is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor, preventing cancer. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.[2] Hence TP53 is classified as a tumor suppressor gene.[3][4][5][6]
The name p53 is in reference to its apparent molecular mass: It runs as a 53-kilodalton (kDa) protein on SDS-PAGE. But, based on calculations from its amino acid residues, p53's mass is actually only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slows its migration on SDS-PAGE, thus making it appear heavier than it actually is.[7] This effect is observed with p53 from a variety of species, including humans, rodents, frogs, and fish.
p53 is also known as:
UniProt name: Cellular tumor antigen p53
Antigen NY-CO-13
Phosphoprotein p53
Transformation-related protein 53 (TRP53)
Tumor suppressor p53

In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1).[3][4][5][6] The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53.[8] TP53 orthologs[9] have been identified in most mammals for which complete genome data are available.
In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility, however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer.[10] A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.[11] A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer.[12] One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women.[13] A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.[14]
Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk[15] and endometrial cancer risk.[16] A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer.[17] Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.[18]
p53 has many mechanisms of anticancer function, and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms:
It can activate DNA repair proteins when DNA has sustained damage.
It can arrest growth by holding the cell cycle at the G21/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).
It can initiate apoptosis, the programmed cell death, if DNA damage proves to be irreparable.

p53 pathway: In a normal cell p53 is inactivated by its negative regulator, mdm2. 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.
Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a,[27] WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK2) and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.
When p21(WAF1) is complexed with CDK2 the cell cannot continue to the next stage of cell division. 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.[28] Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.[29]
Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other.[30]
p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans.[31]
p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning.[32][33]
p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,[34] osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. 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. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.
The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF.
In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), which is itself a product of p53, binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible.
A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.[35]
Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells.
USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cyptoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.[36]
Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.[37] Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.
If the TP53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. The TP53 gene can also be damaged in cells by mutagens (chemicals, radiation, or viruses), increasing the likelihood that the cell will begin decontrolled division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.[38] Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging.[39] However, restoring endogenous p53 function holds a lot of promise. Research has been done to show that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways in which tumor regression occur depends chiefly on tumor type. With restoration of endogenous p53 function, lymphomas exhibit apoptosis and cell growth is lowered to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option.[40][41] Loss of p53 creates genomic instability that most often results in the aneuploidy phenotype.[42]
Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, pRb, by the HPV protein E7, allows for repeated cell division manifested in the clinical disease of warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.[43]
In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop, MDM2 is itself induced by the p53 protein. However, mutant p53 proteins often do not induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.[44]



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