p53 mutations in human cancers

Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.     

p53 regulates mitochondrial respiration

The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.     

FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression

The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.     

Mutational analysis of the tyrosine phosphatome in colorectal cancers

Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice-site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP (PTPRT) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.     

Mutation affecting the 12th amino acid of the c-Ha-ras oncogene product occurs infrequently in human cancer

A point mutation alters the 12th amino acid of the c-Ha-ras oncogene product p21 in a human bladder cancer cell line. This is, at present, the only mutation known to result in a human transforming gene. This mutation may therefore represent a possible target for mutagenesis leading to carcinogenesis in humans. By means of restriction enzyme analysis, 29 human cancers, including 20 primary tumor tissues, derived from organs commonly exposed to environmental carcinogens, were tested for the presence of this mutation. None of ten primary bladder carcinomas exhibited the mutation; nor did nine colon carcinomas or ten carcinomas of the lung. Thus the point mutation affecting the 12th amino acid of the c-Ha-ras gene product, while a valuable model for carcinogenesis, does not appear to play a role in the development of most human epithelial cancers of the bladder, colon, or lung.     

An oncogene-induced DNA damage model for cancer development

Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.     

二甲基亚硝胺及其前驱物在污水处理厂中的研究进展

N-亚硝基二甲胺（NDMA）是一种具有强致癌性的亚硝胺类物质,由于可在饮用水氯化消毒过程中形成进而造成人体危害,引起了人们的高度重视。NDMA主要的前驱物质为二甲胺（DMA）,含有DMA官能团的有机物质也是其前驱物质。最常用的去除NDMA的方法主要有紫外光降解（UV）、反渗透（RO）和吸附等方法,对各种方法进行综述,总结了其优缺点。此外,也论述了已被发现的NDMA的各种前驱物质,总结了NDMA及其前驱物的去除方法,为后续研究方向提出了一定的意见。     

Recognition of a ubiquitous self antigen by prostate cancer-infiltrating CD8+ T lymphocytes

Substantial evidence exists that many tumors can be specifically recognized by CD8+ T lymphocytes. The definition of antigens targeted by these cells is paramount for the development of effective immunotherapeutic strategies for treating human cancers. In a screen for endogenous tumor-associated T cell responses in a primary mouse model of prostatic adenocarcinoma, we identified a naturally arising CD8+ T cell response that is reactive to a peptide derived from histone H4. Despite the ubiquitous nature of histones, T cell recognition of histone H4 peptide was specifically associated with the presence of prostate cancer in these mice. Thus, the repertoire of antigens recognized by tumor-infiltrating T cells is broader than previously thought and includes peptides derived from ubiquitous self antigens that are normally sequestered from immune detection.     

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Carcinoma of the breast and ovary account for one-third of all cancers occurring in women and together are responsible for approximately one-quarter of cancer-related deaths in females. The HER-2/neu proto-oncogene is amplified in 25 to 30 percent of human primary breast cancers and this alteration is associated with disease behavior. In this report, several similarities were found in the biology of HER-2/neu in breast and ovarian cancer, including a similar incidence of amplification, a direct correlation between amplification and over-expression, evidence of tumors in which overexpression occurs without amplification, and the association between gene alteration and clinical outcome. A comprehensive study of the gene and its products (RNA and protein) was simultaneously performed on a large number of both tumor types. This analysis identified several potential shortcomings of the various methods used to evaluate HER-2/neu in these diseases (Southern, Northern, and Western blots, and immunohistochemistry) and provided information regarding considerations that should be addressed when studying a gene or gene product in human tissue. The data presented further support the concept that the HER-2/neu gene may be involved in the pathogenesis of some human cancers.     

茶多酚与银杏叶提取物联用对人乳腺癌细胞增殖的影响

[目的]研究茶多酚与银杏叶提取物联合作用对人乳腺癌细胞MDA-MB-231增殖的影响。[方法]采用MTT法测定茶多酚、银杏叶提取物单独及联合应用对人乳腺癌细胞系MDA-MB-231的抑制作用;利用光镜观察茶多酚、银杏叶提取物对人乳腺癌系MDA-MB-231形态的影响。[结果]MTT法显示银杏叶提取物与低浓度（10、20μg/ml）的茶多酚联合使用,对乳腺癌细胞抑制率明显高于单独用药组,但是联合用药组只有在一定的浓度范围内才会产生协同作用抑制乳腺癌细胞增殖;在细胞形态方面,与单独用药组、对照组相比,联合用药组乳腺癌细胞生长状况差,折光性弱,贴壁细胞皱缩,变圆。[结论]银杏叶提取物在低浓度下对人乳腺癌细胞系MDA-MB-231生长无明显抑制作用,茶多酚和茶多酚联合银杏叶提取物均可抑制MDA-MB-231细胞生长,联合用药组强于单独用药,在一定浓度范围内起协同作用。     

茶氨酸溴香酰胺对人宫颈癌细胞体内外生长的抑制作用

将茶氨酸为母体合成的茶氨酸衍生物茶氨酸溴香酰胺(TBrC)与茶氨酸作比较,评估茶氨酸溴香酰胺对人宫颈癌细胞体内外生长的抑制作用与其分子机制。应用MTT等方法检测不同浓度的TBrC对人宫颈癌细胞体外生长的影响,运用蛋白质印迹法检测解析这些人宫颈癌细胞中与凋亡和生长密切相关蛋白的表达和药物可能的作用靶点。此外,通过建立动物肿瘤模型,评价TBrC对荷瘤裸鼠人宫颈癌生长的抑制效果。实验结果显示,TBrC抑制人宫颈癌细胞体内外生长的活性超过其母体化合物茶氨酸多倍,对小鼠生长无明显毒性;TBrC作用的分子机制之一可能与抑制VEGFR1-Bcl-2/Bax信号传导通路相关。研究结果提示,TBrC具有广泛应用于临床治疗和(或)辅助治疗人宫颈癌和其他癌症的潜力。     

Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit

Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kalpha, with oncogenic mutations identified in both the p110alpha catalytic and the p85alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110alpha in a complex with the p85alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.     

Sustained loss of a neoplastic phenotype by brief inactivation of MYC

Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.