Znhit1 controls meiotic initiation in male germ cells by coordinating with Stra8 to activate meiotic gene expression.

The switch from mitosis to meiosis ensures the successive formation of gametes. However, it remains unclear how meiotic initiation occurs within the context of chromatin. Recent studies have shown that zinc finger HIT-type containing 1 (Znhit1), a subunit of the SRCAP chromatin remodeling complex, plays essential roles in modulating the chromatin structure. Herein, we report that the germline-conditional deletion of Znhit1 in male mice specifically blocks meiotic initiation. We show that Znhit1 is required for meiotic prophase events, including synapsis, DNA double-strand break formation, and meiotic DNA replication. Mechanistically, Znhit1 controls the histone variant H2A.Z deposition, which facilitates the expression of meiotic genes, such as Meiosin, but not the expression of Stra8. Interestingly, Znhit1 deficiency disrupts the transcription bubbles of meiotic genes. Thus, our findings identify the essential role of Znhit1-dependent H2A.Z deposition in allowing activation of meiotic gene expression, thereby controlling the initiation of meiosis.

Depression as a Risk Factor for Developing Heart Failure: A Meta-Analysis of Prospective Cohort Studies.

BACKGROUND: The associations of depression with incident heart failure (HF) risk based on epidemiological studies have been inconsistent. OBJECTIVE: We aimed to quantitatively estimate the relative effect of depression on the development of HF. METHODS: We performed a systematic review and meta-analysis of cohort studies published between January 1, 1950, and August 31, 2019, from PubMed, Embase, and the Science Citation Index databases. We selected prospective cohort studies reporting the relationship between depression and incident HF. Maximally adjusted hazard ratios and their 95% confidence intervals were combined using a random-effects model. The heterogeneity across studies was calculated by the I2 statistic. This meta-analysis was registered in PROSPERO (number CRD42020149274). RESULTS: Six population-based, prospective cohort studies with 4727 HF events among 131 282 participants were eligible for meta-analysis. Compared with participants reporting no depression, those with depression had a 23% increased risk of developing HF (pooled hazard ratio, 1.23; 95% confidence interval, 1.08-1.41). There was no significant heterogeneity across studies (χ2 = 7.75, df = 5, P = .17, I2 = 35.5%). CONCLUSION: Published literature supports a significant association of depression with an increased incidence of HF in the general population.

Somatization disorder mediates the association of depression and anxiety with functional impairment in patients with heart failure.

Previous studies have suggested that depression, anxiety, and somatization disorder are strongly associated with diminished functional status. However, research has not tested the mediational models of how depression and anxiety lead to functional impairment. The aim of this study was to examine whether somatization disorder mediates the association of depression and anxiety with functional impairment in heart failure (HF) patients. The self-reported questionnaires were applied to measure depression, anxiety, and somatization disorder. Functional status was evaluated by the NYHA Class. Ordinal logistic regression analysis was performed to examine the association of depression, anxiety, and somatization disorder with functional status. Mediation analysis was conducted to determine indirect effects. Functional impairment was both related to depression (OR = 2.257, 95% CI = 1.534-3.322, P < 0.001) and elevated somatization severity (OR = 1.042, 95% CI = 1.003-1.082, P = 0.032) in HF patients, whereas anxiety was not associated with functional impairment (OR = 0.659, 95% CI = 0.429-1.012, P > 0.05). Mediation analysis indicated that both depression and anxiety have indirect effects on functional impairment as mediated by somatization disorder in HF patients. Additionally, depression has direct effect on functional impairment of the patients.

The Correct Localization of Borealin in Midbody during Cytokinesis Depends on IQGAP1.

Borealin is a key component of chromosomal passenger complex, which is vital in cytokinesis. IQ domain-containing GTPase-activating protein 1 (IQGAP1) also participates in cytokinesis. The correlation between Borealin and IQGAP1 during cytokinesis is not yet clear. Here, we used mass spectrometry and endogenous coimmunoprecipitation experiments to investigate the interaction between IQGAP1 and Borealin. Results of the current study showed that Borealin interacted directly with IQGAP1 both in vitro and in vivo. Knockdown of IQGAP1 resulted in an abnormal location of Borealin in the midbody. Knocking down Borealin alone, IQGAP1 alone, or Borealin and IQGAP1 at the same time inhibited the completion of cytokinesis and formed multinucleated cells. Our results indicated that IQGAP1 interacts with Borealin during cytokinesis, and the correct localization of Borealin in the midbody during cytokinesis is determined by IQGAP1, and IQGAP1 may play an important role in regulating Borealin function in cytokinesis.

Effect of exogenous hormones on R-spondin 1 (RSPO1) gene expression and embryo development in Pelodiscus sinensis.

Little is known about sex determination and differentiation in the Chinese soft-shelled turtle Pelodiscus sinensis. R-Spondin 1 (RSPO1), a candidate sex-determining gene, is an important regulator of ovarian differentiation in animals. Exogenous drugs can affect sex differentiation. In this study we cloned the RSPO1 gene from P. sinensis (psRSPO1) and analysed its expression profile. The psRSPO1 gene exhibited sequence identity with RSPO1 genes from other species. RSPO1 protein-based phylogenetic analysis showed that psRSPO1 in P. sinensis is closely related to RSPO1 proteins from other turtles. psRSPO1 showed abundant expression in adult brain and gonads, with higher levels in females than males. We also evaluated the effects of three finaconcentration of 2.5, 5.0 and 10mgmL-1 exogenous oestradiol (E2) and aromatase inhibitor (letrozole) on the expression of psRSPO1, external embryo morphology, growth status of embryos and the sex ratio when the drugs were injected to eggs during incubation. The expression of psRSPO1 was upregulated and downregulated by exogenous oestradiol and letrozole respectively, despite inconsistent expression trends at different embryo development times. External embryo morphology, growth status and sex ratio were affected by both exogenous oestradiol and the aromatase inhibitor. Feminisation was induced by oestradiol, but inhibited by letrozole. These results will contribute to studies of the potential molecular mechanisms underlying sex differentiation and sex control in the Chinese soft-shelled turtle.

Pyramidatine (Z88) Sensitizes Vincristine-Resistant Human Oral Cancer (KB/VCR) Cells to Chemotherapeutic Agents by Inhibition of P-glycoprotein.

BACKGROUND: Multi-drug resistance (MDR) remains a major impediment in cancer therapy. A major goal for scientists is to discover more effective compounds that are able to circumvent MDR and simultaneously have minimal adverse side effects. OBJECTIVE: In the present study, we aim to determine the anti-MDR effects of pyramidatine (Z88), a cinnamic acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, on KB/VCR (vincristineresistant human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells. METHODS: Cell viability and average resistant fold (RF) of Z88 were examined by Cell Counting Kit-8 (CCK-8) assay. Flow cytometry, western blot, RT-PCR, Rhodamine 123 accumulation assay and P-glycoprotein (P-gp) ATPase assay were used to demonstrate the anti-MDR activity and mechanism of Z88. RESULTS: The average RF of Z88 is 0.09 and 0.51 in KB/VCR and MCF-7/ADR cells. A CCK-8 assay showed that Z88 could enhance the cytotoxicity of VCR toward KB/VCR cells. A FACS analysis revealed that Z88 could enhance the VCR-induced apoptosis as well as G2/M arrest in a dose-dependent manner in KB/VCR cells. Western blot results showed that the expression levels of PARP, Bax, and cyclin B1 all increased after treatment with 0.2 µmol/L (µM) of VCR combined with 10 µM of Z88 for 24 h in KB/VCR cells. Z88 also could enhance the accumulation of rhodamine 123. Further studies showed that Z88 could inhibit the verapamil stimulated Pgp ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the expression of P-gp at both RNA and protein level. CONCLUSION: Z88 exerted potent anti-MDR activity in vitro and its mechanisms are associated with dualinhibition of the function and expression of P-gp. These findings encourage efforts to develop more effective reversal agents to circumvent MDR based on Z88.

Knockout of the Nogo-B Gene Attenuates Tumor Growth and Metastasis in Hepatocellular Carcinoma.

Human hepatocellular carcinoma (HCC) is a malignant cancer. It is a challenge to develop anti-HCC drugs due to HCC's extreme aggressiveness and with the sensitivity of the liver to show severe adverse effects. More importantly, the precise mechanisms causing HCC pathogenicity are not known. Our previous study disclosed Nogo-B as a reticulon 4 (Rtn4) family member. In the present study, we first identified that Nogo-B played a critical role in HCC progression. We found, via in vitro and in vivo assays, that Nogo-B was expressed aberrantly in primary HCC tumor tissues and immortal HCC cells but was relatively scarce in the normal liver tissues or cells. Nogo-B knockout, via the CRISPR-Cas9 technique, resulted in significant suppression of HCC cell proliferation and tumor growth. Next-generation sequencing analysis showed that Nogo-B knockout have effects on interleukin-6 (IL-6) signaling pathway. Furthermore, we observed that IL-6 induced phosphorylation of STAT3 (pSTAT3) in wild-type HCC cells, but Nogo-B knockout could reduce IL-6-induced increase of pSTAT3, supporting that Nogo-B affects HCC tumor progression possibly via regulating the IL-6/STAT3 signaling pathway. In conclusion, Nogo-B is expressed aberrantly in HCCs and plays an oncogenic role. These findings support that Nogo-B may be a novel anti-HCC therapeutic target.

Meta-analysis of gene expression profiles indicates genes in spliceosome pathway are up-regulated in hepatocellular carcinoma (HCC).

Hepatocellular carcinoma (HCC) is among the commonest kind of malignant tumors, which accounts for more than 500,000 cases of newly diagnosed cancer annually. Many microarray studies for identifying differentially expressed genes (DEGs) in HCC have been conducted, but results have varied across different studies. Here, we performed a meta-analysis of publicly available microarray Gene Expression Omnibus datasets, which covers five independent studies, containing 753 HCC samples and 638 non-tumor liver samples. We identified 192 DEGs that were consistently up-regulated in HCC vs. normal liver tissue. For the 192 up-regulated genes, we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis. To our surprise, besides several cell growth-related pathways, spliceosome pathway was also up-regulated in HCC. For further exploring the relationship between spliceosome pathway and HCC, we investigated the expression data of spliceosome pathway genes in 15 independent studies in Nextbio database ( https://www.nextbio.com/b/nextbioCorp.nb ). It was found that many genes of spliceosome pathway such as HSPA1A, SNRPE, SF3B2, SF3B4 and TRA2A genes which we identified to be up-regulated in our meta-analysis were generally overexpressed in HCC. At last, using real-time PCR, we also found that BUD31, SF3B2, SF3B4, SNRPE, SPINK1, TPA2A and HSPA1A genes are significantly up-regulated in clinical HCC samples when compared to the corresponding non-tumorous liver tissues. Our study for the first time indicates that many genes of spliceosome pathway are up-regulated in HCC. This finding might put new insights for people's understanding about the relationship of spliceosome pathway and HCC.

UNC50 prompts G1/S transition and proliferation in HCC by regulation of epidermal growth factor receptor trafficking.

BACKGROUND: UNC50 has long been recognized as a Golgi apparatus protein in yeast, and is involved in nicotinic receptor trafficking in Caenorhabditis elegans, but little is known about UNC50 gene function in human biology despite it being conserved from yeast to high eukaryotes. OBJECTIVES: We investigated the relation between UNC50 and human hepatocellular carcinoma (HCC) and the potential mechanisms underlying HCC development. METHODS: UNC50 mRNA expression patterns in 12 HCC and adjacent non-cancerous tissues determined using northern blotting were confirmed by real-time PCR in another 44 paired tissues. Microarray experiments were used to screen for global effects of UNC50 knockdown in the Hep3B cell line, and were confirmed by real-time PCR, western blotting, flow cytometry, and tetrazolium assay in both UNC50 overexpression and knockdown Hep3B cells. RESULTS: UNC50 expression levels were upregulated in HCC tissues in comparison with the adjacent non-cancerous tissues. UNC50 knockdown reduced mRNA levels of the downstream targets of the epidermal growth factor receptor (EGFR) pathway: cyclin D1 (CCND1), EGF, matrix metalloproteinase-7 (MMP7), aldose reductase-like 1 (AKR1B10), cell surface-associated mucin 1 (MUC1), and gastrin (GAST). Moreover, UNC50 influenced EGF, inducing cell cycle entry by affecting cell surface EGFR amounts. CONCLUSIONS: UNC50 may plays some roles in HCC progression by affecting the EGFR pathway.

A new small-molecule Aurora B inhibitor shows antitumor activity in human cancer cell lines.

The Aurora kinase family, as a group of serine/threonine kinases regulating cell cycles, are frequently overexpressed or amplified in human tumors. Here, we showed that the small molecule S4 could inhibit Aurora kinase in both of biochemincal and cell-based levels. The Aurora B inhibition of S4 treatment inhibited the phosphorylation of Histone H3 at serine 10 in HeLa and SMMC7721 cells. Cell proliferation assay showed that inhibition of Aurora kinase led to reduced cancer cell growth. As assessed in colony formation experiment, S4 blocked the capability of the HeLa cells to develop colonies. Subsequently, S4 treatment blocked the mitotic G2/M-G1 phase progression which is characterized by the accumulations of cells with 4 N DNA content, induced a cell cycle arrest in a pseudo G1 phase and resulted in apoptotic cell death in a dose- and time-dependent manners. Taken together, this Aurora kinase inhibitor S4 induces growth inhibition of cancer cell line.

Phylogenetic analysis of CDK and cyclin proteins in premetazoan lineages.

BACKGROUND: The molecular history of animal evolution from single-celled ancestors remains a major question in biology, and little is known regarding the evolution of cell cycle regulation during animal emergence. In this study, we conducted a comprehensive evolutionary analysis of CDK and cyclin proteins in metazoans and their unicellular relatives. RESULTS: Our analysis divided the CDK family into eight subfamilies. Seven subfamilies (CDK1/2/3, CDK5, CDK7, CDK 20, CDK8/19, CDK9, and CDK10/11) are conserved in metazoans and fungi, with the remaining subfamily, CDK4/6, found only in eumetazoans. With respect to cyclins, cyclin C, H, L, Y subfamilies, and cyclin K and T as a whole subfamily, are generally conserved in animal, fungi, and amoeba Dictyostelium discoideum. In contrast, cyclin subfamilies B, A, E, and D, which are cell cycle-related, have distinct evolutionary histories. The cyclin B subfamily is generally conserved in D. discoideum, fungi, and animals, whereas cyclin A and E subfamilies are both present in animals and their unicellular relatives such as choanoflagellate Monosiga brevicollis and filasterean Capsaspora owczarzaki, but are absent in fungi and D. discoideum. Although absent in fungi and D. discoideum, cyclin D subfamily orthologs can be found in the early-emerging, non-opisthokont apusozoan Thecamonas trahens. Within opisthokonta, the cyclin D subfamily is conserved only in eumetazoans, and is absent in fungi, choanoflagellates, and the basal metazoan Amphimedon queenslandica. CONCLUSIONS: Our data indicate that the CDK4/6 subfamily and eumetazoans emerged simultaneously, with the evolutionary conservation of the cyclin D subfamily also tightly linked with eumetazoan appearance. Establishment of the CDK4/6-cyclin D complex may have been the key step in the evolution of cell cycle control during eumetazoan emergence.

T-LAK cell-originated protein kinase is essential for the proliferation of hepatocellular carcinoma SMMC-7721 cells.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and typically has poor prognosis. Like most cancers, altered gene expression was always associated with the induction and maintenance of HCC. Here, we reported that the expression level of T-LAK cell-originated protein kinase (TOPK) is significantly up-regulated in human HCC samples and cell lines. The suppression of TOPK by short hairpin RNA in HCC cell line SMMC-7721 caused cell cycle arrest and reduced cell growth and colony formation ability. Moreover, the tumor formation ability of the TOPK-suppression cells was significantly impaired compared with the control cells in nude mice. In addition, the knockdown expression of TOPK reduced the AKT phosphorylation. Taken together, we unveiled a novel role of TOPK which acts as an important positive regulator in human HCC cell proliferation.

IL-2 mRNA stabilization upon PMA stimulation is dependent on NF90-Ser647 phosphorylation by protein kinase CbetaI.

IL-2 is an important cytokine produced in T cells in response to Ag or mitogen stimulation. It is regulated at both transcriptional and posttranscriptional levels. One of the key regulators of IL-2 mRNA stability is NF90. Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it. Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser(647) and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. Phorbol ester (PMA) is a protein kinase C (PKC) activator. Through transcription activation and mRNA stabilization, IL-2 mRNA levels increase promptly when T cells are stimulated with PMA. However, how PMA stabilizes IL-2 mRNA was still unclear. In this study, we demonstrate that PMA stimulation led to phosphorylation of NF90 at Ser(647) via PKCßI. This phosphorylation was necessary for nuclear export of NF90 in response to PMA and for IL-2 mRNA stabilization. We show that phosphorylation at NF90-Ser(647) upregulated IL-2 production in response to PMA stimulation. Our results support a model in which PMA stimulation activates PKCßI to phosphorylate NF90-Ser(647), and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA. Thus, our study elucidates the mechanism by which PMA activates and stabilizes IL-2 expression in T cells.

The ancient function of RB-E2F pathway: insights from its evolutionary history.

BACKGROUND: The RB-E2F pathway is conserved in most eukaryotic lineages, including animals and plants. E2F and RB family proteins perform crucial functions in cycle controlling, differentiation, development and apoptosis. However, there are two kinds of E2Fs (repressive E2Fs and active E2Fs) and three RB family members in human. Till now, the detail evolutionary history of these protein families and how RB-E2F pathway evolved in different organisms remain poorly explored. RESULTS: We performed a comprehensive evolutionary analysis of E2F, RB and DP (dimerization partners of E2Fs) protein family in representative eukaryotic organisms. Several interesting facts were revealed. First, orthologues of RB, E2F, and DP family are present in several representative unicellular organisms and all multicellular organisms we checked. Second, ancestral E2F, RB genes duplicated before placozoans and bilaterians diverged, thus E2F family was divided into E2F4/5 subgroup (including repressive E2Fs: E2F4 and E2F5) and E2F1/2/3 subgroup (including active E2Fs: E2F1, E2F2 and E2F3), RB family was divided into RB1 subgroup (including RB1) and RBL subgroup (including RBL1 and RBL2). Third, E2F4 and E2F5 share more sequence similarity with the predicted E2F ancestral sequence than E2F1, E2F2 and E2F3; E2F4 and E2F5 also possess lower evolutionary rates and higher purification selection pressures than E2F1, E2F2 and E2F3. Fourth, for RB family, the RBL subgroup proteins possess lower evolutionary rates and higher purification selection pressures compared with RB subgroup proteins in vertebrates, CONCLUSIONS: Protein evolutionary rates and purification selection pressures are usually linked with protein functions. We speculated that function conducted by E2F4/5 subgroup and RBL subgroup proteins might mainly represent the ancient function of RB-E2F pathway, and the E2F1/2/3 subgroup proteins and RB1 protein might contribute more to functional diversification in RB-E2F pathway. Our results will enhance the current understanding of RB-E2F pathway and will also be useful to further functional studies in human and other model organisms.

Meta-analysis of association between matrix metalloproteinases 2, 7 and 9 promoter polymorphisms and cancer risk.

Matrix metalloproteinase (MMP) 2, MMP7 and MMP9 are important members of the MMP family. Four polymorphisms in the promoter region of these MMPs, which are MMP2 -1306 C>T, MMP2 -735 C>T, MMP7 -181 A>G and MMP9 -1562 C>T, have been reported to be functional and may contribute to genetic susceptibility to cancers. However, the associations between these polymorphisms and cancer risk remain inconclusive due to conflicting results from different case-control studies. To better evaluate the role of these polymorphisms in cancer development, we conducted a meta-analysis that included 51 studies, with more than 40,000 subjects. The results showed that under dominant genetic model, MMP2 -1306 T was associated with lower susceptibility to lung cancer [odds ratio (OR) = 0.50, 95% confidence interval (CI) 0.43-0.59, P(heterogeneity) = 0.147, I(2) = 44.1%], head and neck cancer (OR = 0.53, 95% CI 0.41-0.69, P(heterogeneity) = 0.974, I(2) = 0.0%) and oesophageal cancer (OR = 0.67, 95% CI 0.55-0.80, P(heterogeneity) = 0.593, I(2) = 0.0%); MMP2-735T was associated with lower risk in lung cancer (OR = 0.65, 95%CI 0.53-0.79, P(heterogeneity) = 0.42, I(2) = 0.0%) and oesophageal cancer (OR = 0.84, 95% CI 0.70-0.99, P(heterogeneity) = 0.206, I(2) = 37.4%); MMP7 -181 AG and GG genotype carriers had an increased gastric cancer risk (OR = 1.90, 95% CI 1.43-2.51, P(heterogeneity) = 0.992, I(2) = 0.0%) and MMP9 -1562 C>T was not associated with cancer risk in the whole group analysis (OR = 0.99, 95% CI 0.91-1.08, P(heterogeneity) = 0.419, I(2) = 3.0%) and subgroup analyses. In all, our meta-analysis suggests that MMP2 -1306 C>T, MMP2 -735 C>T and MMP7 -181 A>G may play allele-specific roles in cancer development, while MMP9 -1562 C>T may not be a major risk factor for most cancer types. Large case-control studies should be performed to clarify the possible roles of these four polymorphisms in different kinds of cancer in more detail.

The association between HSD17B1 Ser312Gly polymorphism and breast cancer risk: a meta-analysis including 31,053 subjects.

There are increasing evidences that HSD17B1 plays a significant role in the development of breast cancer. However, published data on the association between HSD17B1 Ser312Gly polymorphism and breast cancer risk are inconclusive. In order to derive a more precise estimation of this relationship, a meta-analysis including 9 studies with 31,053 subjects was performed in this study. Crude ORs with 95% CIs were used to assess the strength of association between HSD17B1 Ser312Gly polymorphism and breast cancer risk. The pooled ORs were performed for codominant model (Gly/Gly versus Ser/Ser, Gly/Ser versus Ser/Ser), dominant model (Gly/Gly + Gly/Ser versus Ser/Ser), and recessive model (Gly/Gly versus Gly/Ser + Ser/Ser), respectively. Overall, no significant associations were detected between HSD17B1 Ser312Gly polymorphism and breast cancer susceptibility. However, in the stratified analysis by ethnicity, significant associations were observed in Caucasians for Gly/Gly versus Ser/Ser (OR = 0.91; 95% CI 0.83-1.00), Gly/Ser versus Ser/Ser (OR = 0.92; 95% CI 0.85-0.99), and Gly/Gly + Gly/Ser versus Ser/Ser (OR = 0.92; 95% CI 0.86-0.98). In conclusion, this study suggests that HSD17B1 312Gly allele may be a protective factor for breast cancer development in Caucasians. However, large sample and representative population-based studies with homogeneous breast cancer patients and well-matched controls are warranted to confirm this finding.

Polymorphisms in the promoter regions of matrix metalloproteinases 1 and 3 and cancer risk: a meta-analysis of 50 case-control studies.

Matrix metalloproteinase (MMP) 1 and MMP3 are enzymes that degrade the extracellular matrix and have been implicated to play an important role in cancer development. Many studies have been carried out on the association between polymorphisms of MMP1 -1607 1G>2G and MMP3 -1171 5A>6A and cancer risk. However, results from these studies remain inconclusive. Here, we performed a meta-analysis of >38 000 subjects to better assess the purported associations. For MMP1, -1607 2G/2G genotype carriers were found to have an increased risk of colorectal cancer [2G/2G versus 2G/1G + 1G/1G, odds ratio (OR) = 1.48, 95% confidence interval (CI) (1.26-1.74), P(heterogeneity) = 0.066, I(2) = 49.3%], head and neck cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.61, 95% CI (1.26-2.07), P(heterogeneity) = 0.002, I(2) = 64.7%] and renal cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.82, 95% CI (1.38-2.39), P(heterogeneity) = 0.589, I(2) = 0.0%] risk. For MMP3, no association was found between -1171 5A>6A polymorphism and cancer risk in the overall group [6A versus 5A, OR = 1.00, 95% CI (0.95-1.05), P(heterogeneity) = 0.124, I(2) = 24.9%] and individual cancer subgroups, but stratified analysis by smoking status showed that this polymorphism had different effects on smokers and non-smokers under recessive genetic model. In summary, our study suggests that MMP1 -1607 2G may be associated with an increased cancer risk for certain types of cancers, MMP3 -1171 5A>6A may not be a major risk factor for cancer, but it may be modified by certain environmental factors. Future studies with larger sample sizes are warranted to further evaluate these associations in more detail.

The evolution, complex structures and function of septin proteins.

The septin family is a conserved GTP-binding protein family and was originally discovered through genetic screening for budding yeast mutants. Septins are implicated in many cellular processes in fungi and metazoa. The function of septins usually depends on septin assembling into oligomeric complexes and highly ordered polymers. The expansion of the septin gene number in vertebrates increased the complex diversity of septins. In this review, we first discuss the evolution, structures and assembly of septin proteins in yeast and metazoa. Then, we review the function of septin proteins in cytokinesis, membrane remodeling and compartmentalization.

The evolution of BIR domain and its containing proteins.

BIR domain and its containing proteins play critical roles in cell apoptosis and cell division. Here several lines of novelty were revealed based on a comprehensive evolutionary analysis of BIR domains in 11 representative organisms. First, the type II BIR domains in Survivin and Bruce showed more conservation compared with the type I BIR domains in the inhibitors of apoptosis proteins (IAPs). Second, cIAP was derived from a XIAP duplicate and emerged just after the divergence of invertebrates and vertebrates. Third, the three BIR domains of NAIP displayed significantly elevated evolutionary rates compared with the BIR domains in other IAPs.

GTP binding is required for SEPT12 to form filaments and to interact with SEPT11.

Septins are a family of filament-forming GTP-binding proteins involved in a variety of cellular process such as cytokinesis, exocytosis, and membrane dynamics. Here we report the biochemical and immunocytochemical characterization of a recently identified mammalian septin, SEPT12. SEPT12 binds GTP in vitro, and a mutation (Gly56 to Asn) in the GTP-binding motif abolished binding. Immunocytochemical analysis revealed that wild-type SEPT12 formed filamentous structures when transiently expressed in Hela cells whereas SEPT12G56A generated large aggregates. In addition, wild-type SEPT12 failed to form filaments when coexpressed with SEPT12G56A. We also observed that GTP-binding by SEPT12 is required for interaction with SEPT11 but not with itself.