Axin bridges Daxx to p53

The death domain-associated protein Daxx exerts many reported functions that include mediating the signaling from FasL to apoptosis via activating the c-Jun N-terminal kinase （JNK） [1], induction and inhibition of apoptosis [2-5], and regulation of chromatin remodeling. It was originally cloned from a yeast two-hybrid screen using the intracellular tail of the Fas receptor as the bait [1]. Whereas many of the initial reports remain controversial, it is clear that Daxx plays important roles in the regulation of apoptosis triggered by a series of stress signals including UV irradiation, hydrogen peroxide treatment and TGF-β treatment [2, 3]. In this Commentary, we focus on Axin being a tethering factor linking Daxx to p53.     

PanK4 inhibits pancreatic beta-cell apoptosis by decreasing the transcriptional level of pro-caspase-9

Dear Editor： Coenzyme A （CoA） is a primary and predominant acyl group carrier involved in a wide variety of important biochemical processes. The CoA biosynthetic pathway is composed of five enzymatic steps, of which Pantothenate kinase （PanK） is a key regulatory enzyme. The multiple isoforms of PanK are encoded by four different genes [1,2]. In our previous studies of SNP markers by genotyping the case-controlled DNAs, we found that one SNP within the hPANK4 gene on chromosome 1 was associated with type 2 diabetes [3-5]. We subsequently showed that rat PanK4 （rPanK4） was up-regulated when rats were challenged by high concentration of glucose [6]. M2-type pyruvate kinase （Pkm2） was found, both in vitro and in vivo, to be associated with rPanK4 [7]. These data suggest that PanK4 may have a role in diabetes pathogenesis. The development of type 2 diabetes is due partly to the loss of the pancreatic β-cell mass, therefore the secreted amount of insulin is insufficient to maintain the glucose homoestasis [8]. In the present study, we evaluated the effect ofrPanK4 on β-cell apoptosis. We aimed to determine the potential ofrPanK4 gene in β-cell apoptosis induced by the cytotoxic agent streptozotocin （STZ）.[第一段]     

T-DNA-Induced Chromosomal Translocations in feronia and anxur2 Mutants Reveal Implications for the Mechanism of Collapsed Pollen Due to Chromosomal Rearrangements

Dear Editor, Approximately every fifth Arabidopsis T-DNA inser- tion line contains chromosomal translocations caused by the inserted T-DNA （Clark and Krysan, 2010）. Albeit broad use of T-DNA lines for mutant analysis, little is known about the consequences of these chromosomal rearrangements and only a few studies describe chromosomal aberrations in the mutant lines. While plant growth in general is not affected by such chromosomal translocations, defects in gametophyte development have been observed in lines that are heterozygous for the T-DNA insertion （Ray et al., 1997; Curtis et al., 2009）.     

PTEN, a general negative regulator of cyclin D expression

The tumor-suppressor phosphatase with tensin homology （PTEN） is frequently mutated in many malignancies and is one of the most well studied tumor suppressor genes [ 1, 2]. PTEN, a lipid and protein dual phosphatase, plays a vital role in embryonic development, cell growth, apoptosis and cell migration. The well-known function of PTEN is phosphatidylinositol-3 （PI3）-phosphatase, which functions as a negative regulator of the PI3 kinase （PI3K） pathway. It is well established that PTEN regulates the G I-S transition by modulating the expression of cyclin D 1 and p27gipl.     

A novel member of lymphocyte-specific protein tyrosine kinase protein identified in lamprey,Lampetrajaponica

Lymphocyte-specific protein tyrosine kinase p56 （Lck） is a member of the Src family of non-receptor protein tyrosine kinase. Lck plays an important role in mediating T-cell recep- tor （TCR） signal tmnsduction and the development, differenti- ation, proliferation, and activation of T-cells [ 1 ]. Lck contains N-terminus of myristylation sequence, a unique amino- terminus region, followed by Src homology 3 （SH3） and SH2 domains and a C-terminus oftyrosine kinase catalytic domain [2].     

Shp2, a novel oncogenic tyrosine phosphatase and potential therapeutic target for human leukemia

Shp2, encoded by the PTPNll gene in human, is a ubiquitously expressed protein tyrosine phosphatase that contains two N-terminal Src homology 2 （SH2） domains （N-SH2, C-SH2, respectively）, a catalytic protein-tyrosine phosphatase （PTP） domain, and a C-terminal tail with tyrosyl phosphorylation sites and a prolyl-rich motif [1]. The progress of our understanding of biological functions of Shp2 has clearly shown that Shp2 plays an important role not only in biology of normal hematopoietic cells and other mammalian cells, but also in the development of leukemia and other tumors. Most recently, PTPNll gene has been firmly established as the first proto-oncogene that encodes a protein tyrosine phosphatase [1-3]. In the hematopoietic system, most if not all function of Shp2 is to act as a positive component that is essential for proliferation and/or survival of hematopoietic cells through regulation of signaling pathways involving Erk, Akt and STATS [ 1-4]. Over the past few years, a number of disease-associated Shp2 mutants have been identified in human leukemia and other malignancies [1, 3, 4]. Recently, studies from our laboratories and others strongly suggest that dysregulation of wild-type Shp2 enzyme may be involved in the pathogenesis of adult leukemia [4-7]. These findings not only provide new insights into the role of Shp2 in leukemogenesis and other tumors, but also suggest new therapeutic targets for anti-leukemia drugs.     

Raloxifene hydrochloride treatment leads to better outcomes than medroxyprogesterone acetate when paired with estrogen in ovariectomized cholesterol-fed rabbits

The benefits of estrogen in cardiovascular system include a reduction in low-density lipoprotein cholesterol （LDL-C）, decrease in LDL oxidation, and enhancement of vascular function [1]. Estrogen replacement therapy, however, has been linked to an increased risk of tissue-specific side effects including breast cancer and uterine cancer [2]. These issues have led to the development of hormone replacement therapy （HRT） which combines estrogen and progestin. Progestin can reverse endometrial hyperplasia induced by estrogen. The most commonly used progestin in HRT is medroxyprogesterone acetate （MPA）, a synthetic progestin, although there is some evidence that the administration of MPA is not as beneficial as natural progesterone [3]. Findings from randomized placebo-controlled trials have demonstrated that the combination of estrogen and MPA does not confer cardiac protection and may increase the risk of coronary heart disease among healthy postmenopausal women, especially in the first year after initiation of hormone therapy. Furthermore, an increase in the risk of breast cancer was also found with this therapy [4]. Although the role of progestin remains poorly defined, it is possible that the coadministration of progestin could counteract the cardioprotective effects of estrogen .     

Association of SOST gene polymorphisms with peak bone mineral density in Chinese nuclear families with male-offspring

Peak bone mineral density(BMD)achieved during early adulthood is a highly heritable trait and a strong determinant of subsequent osteoporotic fracture risk.Evidence has already suggested that 50–80% of the variance in peak BMD is genetically determined [1].Human SOST gene comprises three exons and two introns,mapping to chromosomal region 17q12–q21.It inhibits osteoblastic bone formation by inhibiting the Wnt signaling pathway,which is critically important for the development and function of osteoblasts [2].Our previous study in large samples of postmenopausal Chinese women showed that the polymorphisms in the SOST gene are associated with BMD of the lumbar spine [3],but little is known in men.Thus,the objective of this study was to investigate whether polymorphisms in the SOST gene are associated with variations of peak BMD in Chinese nuclear families with male-offspring.     

Geldanamycin induces CHOP expression through a 4-（2-aminoethyl）-benzenesulfonyl fluoride-responsive serine protease

Dear Editor： Geldanamycin is a benzoquinone ansamycin, which was originally described as a tyrosine kinase inhibitor. However, subsequent studies have revealed that geldanamycin binds to and inhibits heat-shock protein 90 （Hsp90） activity [1]. Hsp90 is a molecular chaperone involved in the conformational maturation of proteins such as mutated p53, Raf- 1, Akt, Bcr-Abl, and ErbB2. It is suggested that agents inhibiting Hsp90 have anti-cancer properties, although the precise molecular mechanisms underlying the anti-cancer effects of geldanamycin are not well understood.     

Oncoprotein p28^GANK binds to RelA and retains NF-κB in the cytoplasm through nuclear export

p28^GANK （also known as PSMD 10, p28 and gankyrin） is an ankyrin repeat anti-apoptotic oncoprotein that is commonly overexpressed in hepatocellular carcinomas and increases the degradation of p53 and Rb. NF-IκB （nuclear factor-κB） is known to be sequestered in the cytoplasm by IκB （inhibitor of NF-κB） proteins [1, 2], but much less is known about the cytoplasmic retention of NF-κB by other cellular proteins. Here we show that p28^GANK inhibits NF-κB activity. As a nuclear-cytoplasmic shuttling protein, p28^GANK directly binds to NF-κB/RelA and exports RelA from nucleus through a chromosomal region maintenance-1 （CRM-1） dependent pathway, which results in the cytoplasmic retention of NF- κB/RelA. We demonstrate that all the ankyrin repeats of p28^GANK are required for the interaction with RelA and that the N terminus of p28^GANK, which contains the nuclear export sequence （NES）, is responsible for suppressing NF-κB/RelA nuclear translocation. These results suggest that overexpression of p28^GANK prevents the nuclear localization and inhibits the activity of NF-κB/RelA.