Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6.

Wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene. Although the normal roles of tumour suppressor genes are still largely unknown, it seems that they could be involved in promoting cell differentiation as well as in mediating growth arrest by growth-inhibitory cytokines. Hence, the abrogation of wild-type p53 expression, which is a common feature of many tumours, could eliminate these activities. We have now tested this notion by restoring the expression of p53 in a murine myeloid leukaemic cell line that normally lacks p53. The use of a temperature-sensitive p53 mutant allowed us to analyse cells in which the introduced p53 had either wild-type or mutant properties. Although there seemed to be no effect on differentiation, the introduction of wild-type p53 resulted in rapid loss of cell viability in a way characteristic of apoptosis (programmed cell death). The effect of wild-type p53 was counteracted by interleukin-6. Thus products of tumour suppressor genes could be involved in restricting precursor cell populations by mediating apoptosis.     

转染野生型p53基因对人白血病细胞系生长的影响

目的研究转染野生型p53基因对人白血病细胞的生长影响作用．方法将克隆有野生型p53基因的pUHD10-3质粒,通过Lipofectin转染人白血病细胞株U937、K562、HL60,用四甲基偶氮唑（Mlvr）法观察细胞的生长情况．结果转染野生型p53基因,可使人白血病细胞U937、K562、HL60的生长明显受到抑制,第4天生长抑制率分别是28．6％、44．9％及49．0％．结论转染野生型p53基因能有效抑制人白血病细胞U937、K562、HL60的生长．     

p53振子的形成机制及microRNA对p53目标基因表达的精细调控

肿瘤抑制因子p53调控着大量的基因,在肿瘤抑制中起着关键作用.实验结果表明,当DNA受损后,p53的表达呈现周期性振荡.已有的一些p53振子的理论模型,其振子产生机制通常依赖于p53和Mdm2之间相互作用的时滞因素.考虑基因表达的转录和翻译过程,运用动力学方程建模的方法,给出一种新模型,并利用Hopf分叉理论,给出p53振子产生的条件.数值模拟结果表明,与已有的时滞模型相比,该模型对参数具有更好的鲁棒性,较好地解释了p53振子的产生机制.最近的许多实验表明,p53调控着miR-34家族中大量microRNA的表达,这些microRNA又在后转录水平上对p53的下游目标基因起着调控作用.在这一模型基础上,研究microRNA加入p53调控网络后所起的调控作用,数值模拟结果初步表明,microRNA对p53下游目标基因表达起到了精细调控作用.     

Mutational hotspot in the p53 gene in human hepatocellular carcinomas.

Human hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G----T transversion in seven HCC DNA samples and the G----C transversion in the other HCC are consistent with mutations caused by aflatoxin B1 in mutagenesis experiments. No mutations were found in exons 5,6,8 or the remainder of exon 7. These results contrast with p53 mutations previously reported in carcinomas and sarcomas of human lung, colon, oesophagus and breast; these are primarily scattered over four of the five evolutionarily conserved domains, which include codon 249 (refs 4-9). We suggest that the mutant p53 protein may be responsible for a selective clonal expansion of hepatocytes during carcinogenesis.     

Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization

The p53 tumour suppressor is a short-lived protein that is maintained at low levels in normal cells by Mdm2-mediated ubiquitination and subsequent proteolysis. Stabilization of p53 is crucial for its tumour suppressor function. However, the precise mechanism by which ubiquitinated p53 levels are regulated in vivo is not completely understood. By mass spectrometry of affinity-purified p53-associated factors, we have identified herpesvirus-associated ubiquitin-specific protease (HAUSP) as a novel p53-interacting protein. HAUSP strongly stabilizes p53 even in the presence of excess Mdm2, and also induces p53-dependent cell growth repression and apoptosis. Significantly, HAUSP has an intrinsic enzymatic activity that specifically deubiquitinates p53 both in vitro and in vivo. In contrast, expression of a catalytically inactive point mutant of HAUSP in cells increases the levels of p53 ubiquitination and destabilizes p53. These findings reveal an important mechanism by which p53 can be stabilized by direct deubiquitination and also imply that HAUSP might function as a tumour suppressor in vivo through the stabilization of p53.     

胃癌中p53基因失活及其蛋白产物的免疫组化分析

应用ＰＣＲ－ＳＳＣＰ银染，Ｓｏｕｔｈｅｒｎ杂我及免疫组化等方法同步研究２５例胃癌标本的ｐ５３基因突变，杂合性丢失及蛋白持表达，在２２例胃癌中同时获得有关ｐ５３基因突变和杂合性丢失的检测结果，被检出ｐ５３基因突变的５例胃癌中，２例伴有杂合性丢失，３例仅有ｐ５３基因突变。     

p53 mutant mice that display early ageing-associated phenotypes.

The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.     

The p53 tumour suppressor gene

The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.     

p53抗体与恶性肿瘤

p53基因是人类肿瘤中突变频率最高的抑癌基因,几乎发生于所有的恶性肿瘤.突变基因编码的p53蛋白释放入血,可诱发机体自身免疫应答,产生p53自身抗体.在肿瘤病人和高危人群中检测血清p53抗体可以反映早期p53基因突变,作为一种新的肿瘤生物学指标,p53抗体有望在恶性肿瘤的早期诊断、治疗、预后、监测、复发等方面发挥重要作用.