张健
现代分子生物学
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- 姓名:张健
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学术头衔:
博士生导师
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学科领域:
光学
- 研究兴趣:现代分子生物学
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13
张健, Sanjay Anand*, Wayne C. H. Wang*, Dennis R. Powell*, Stacey A. Bolanowski*, Jian Zhang*†, Christina Ledje‡, Aruna B. Pawashe§, Chris T. Amemiya¶, and Cooduvalli S. Shashikant*
15666-15669 PNAS December 23, 2003 vol. 100 no.26,-0001,():
-1年11月30日
There is considerable interest in understanding how cis-regulatory modifications drive morphological changes across species. Because developmental regulatory genes, including Hox genes, are remarkably conserved, their noncoding regulatory regions are likely sources for variations. Modifications of Hox cis-regulatory elements have potential to alter Hox gene expression and, hence, axial morphologies. In vertebrates, differences in the axial levels of Hox gene expression correlate with differences in the number and relative position of thoracic vertebrae. Variation in cis-regulatory elements of Hox genes can be identified by comparative sequence and reporter gene analyses in transgenic mouse embryos. Using these approaches, we show a remarkable divergence of the Hoxc8 early enhancers between mammals and fishes representing diverse axial morphologies. Extensive restructuring of the Hoxc8 early enhancer including nucleotide substitutions, inversion, and divergence result in distinct patterns of reporter gene expression along the embryonic axis. Our results provide an evolutionary perspective on how the enhancer elements are engineered and support the hypothesis that remodeling of Hox regulatory elements in different species has played a significant role in generating morphological diversity.
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张健, J. Zhang, and T. Williams, *
DEVELOPMENTAL DYNAMICS 228: 194-207, 2003,-0001,():
-1年11月30日
Mice lacking transcription factor AP-2α exhibit defects in the formation of the head, body wall, heart, neural tube, eye, and limbs, reflecting important sites of AP-2α expression in the developing embryo. AP-2α is also expressed in the postnatal mammary gland and has been linked to tumor progression and defects in growth regulation in the breast. We have used a transgenic mouse approach to identify tissue-specific cis-acting sequences associated with expression of the human AP-2α gene. Our analysis indicates that multiple elements located throughout the gene contribute to expression in the trigeminal ganglia, spinal cord, mammary gland, and epidermis. A discrete cis-element located within the fifth intron is required for expression in the face and limbs, and we have derived a permanent line of AP-2α: lacZ transgenic mice to assess expression of this latter enhancer throughout morphogenesis. We also introduced this transgene into an AP-2α-null mouse background and detected subtle alterations of its expression within the progress zone and apical ectodermal ridge of the forelimbs. Similar changes in lacZ expression were observed within the zeugopod, and these correlated with defects in radius condensation in AP-2α-knockout mice. Taken together, these findings indicate that cell:cell communication within the forelimb is altered in the absence of AP-2α and reveal novel regulatory potential for AP-2α in limb development.
lacZ reporter, transgenic mouse, AP-2α, trans, c, r, i, p, t, ion factor, limb, face, mammary gland, spinal cord, gene expression, regulatory elements
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【期刊论文】Overexpression of transcription factor AP-2α suppresses mammary galnd growth and morphogenesis
张健, J. Zhang, a, S. Brewer, J. Huang, b, and T. Williams a, *
Developmentl Biology 256(2003)127-145,-0001,():
-1年11月30日
AP-2 transciription factors are key regulatrs of mouse embryonic development,Aberrant expression of these genes has also been linked to the progression of human breast cancer. Here, we have investigated the role of the AP-2 geme family in the postnatal maturation of the virgin and pregnant mice. Subsequently, AP-2 expression declines during lactation and then is reactivated during involution. The AP-2α and AP-2γ proteins are localized in the ductal epithlium, as well as in the terminal end buds, suggesting that they may infuence growth of the ductalnetwork. We have tested this hypothesis by targeting AP-2α expression to the mouse mammary gland using the MMTV promoter. Ourstudies indicate that overexpresion of AP-2α inhibits mammary gland growth and morphogenesis, and this coincides with a rise in PTHrP expression. Alveolar buding is severly curtailed in transgenic virgin mice, while lobuloalveolar development and functional differentiation are inhibited druing preganancy and lactation, repectiely. Our studies strongly support a role for the AP-2 proteins in regulating the proliferation and differenatation of mammary gland epithelial cells in both mouse and human.
Transciption factors, AP-2α, AP-2γ,, Transgenic mice, Mammary gland, Alveolar budding, Lobuloalveolar development, Breast cancer
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张健, DOMINIC W. CHUNG*, JIAN ZHANG†, CHENG-KEAT TAN‡, EARL W. DAVIE*, ANTERO G. So†‡ AND KATHLEEN M. DOWNEY†‡
Proc. Natl. Acad. Sci. USA Vol. 88, pp. 11197-11201, December 1991 Biochemistry,-0001,():
-1年11月30日
The catalytic subunit (Mr≈124,000) of human DNA polymerase б has been cloned by PCR using poly(A)+ RNA from HepG2 cells and primers designed from the amino acid sequence of regions highly conserved between bovine and yeast DNA polymerase б. The human cDNA was 3443 nucleotides in length and coded for a polypeptide of 1107 amino acids. The enzyme was 94% identical to bovine DNA polymerase б; and contained the numerous highly conserved regions previously observed in the bovine and yeast enzymes. The human enzyme also contained two putative zinc-finger domains in the carboxyl end of the molecule, as well as a putative nuclear localization signal at the amino-terminal end. The gene coding for human DNA polymerase б was localized to chromosome 19.
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张健, Jian Zhang, § Dominic W. Chung, ║ Cheng-Keat Tan, ┴ Kathleen M. Downey, §, ┴ Earl W. Davie, ║ and Antero G. So*, ┴
Biochemistry 1991, 30, 11742-11750,-0001,():
-1年11月30日
The 125- and 48-kDa subunits of bovine DNA polymerase б have been isolated by SDSpolyacrylamide gel electrophoresis and demonstrated to be unrelated by partial peptide mapping with N-chlorosuccinimide. A 116-kDa polypeptide, usually present in DNA polymerase б preparations, was shown to be a degraded form of the 125-kDa catalytic subunit. Amino acid sequence data from Staphylococcus aureus V8 protease, cyanogen bromide, and trypsin digestion of the 125- and 116-kDa polypeptides were used to design primers for the polymerase chain reaction to determine the nueleotide sequence of a full-length eDNA encoding the catalytic subunit of bovine DNA polymerase б. The predicted polypeptide is 1106 amino acids in length with a calculated molecular weight of 123 707. This is in agreement with the molecular weight of 125 000 estimated from SDS-polyacrylamide gel electrophoresis. Comparison of the deduced amino acid sequence of the catalytic subunit of bovine DNA polymerase б with that of its counterpart from Saccharomyces cerevisiae showed that the proteins are 44% identical. The catalytic subunit of bovine DNA polymerase б contains the seven conserved regions found in a number of bacterial, viral, and eukaryotic DNA polymerases. It also contains five additional regions that are highly conserved between bovine and yeast DNA polymerase б, but these regions share little or no homology with the a polymerases. Four of these additional regions are also highly homologous to the herpes virus family of DNA polymerases, whereas one region is not homologous to any other DNA polymerase that has been sequenced thus far. The polypeptide also contains two C-terminal clusters of cysteine residues postulated to be DNA binding sites or zinc fingers.
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【期刊论文】Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2
张健, Jian Zhang*, Stephanic Hagopian-Donaldson*, George Serbedzija†, Jennifer Elsemore‡, Debora Plehn-Dujowich*, Andrew P. McMahon†, Richard A. Flalvell‡ & Trevor Williams*
NATURE,-0001,():
-1年11月30日
The retinoic acid-indcible transcription factor AP-2 isexpressed in epithlial and neural crest cell linegages during murine development1-5. AP-2 can regulate neural and epithelial gene transcriptio, and is associated with overexpression of c-erbB-2 in human breast-cancer cel lines4-6. To ascertain the importance of AP-2 in human breast-cancer cell lines4-6. To ascertain the importance of AP-2 for normal development, we have derived mice containing a homozygous disruption of the AP-2 gene. These AP-2-ull mice have multpie congenitL development, w have derived mice containing a homzygous disruption of the AP-2 gene. These AP-2 null mice have multiple congenital defect and die at birth. In particuar the AP-2 knockout mice exhibit anencephay, craniorfacia defects and thoraco-abdominoschisis. Skeletal defects occur in the head and trunk region, where many bones are deformed ofabsent. Analysis of tese mice earlier in embryogenesis indicates a failure of cranial neural-ture closure and defect in cranial ganglia development. We have shown that Ap-2 is fundamental regulator of manmmalian craniofacia development.
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张健, Jianlin Zhou a, , Changzheng Fan a, Yingli Zhong a, Yunhai Liu a, Mingjun Liu a, Aidong Zhou a, Kaiqun Ren a, Jian Zhang a, b, *
FEBS Letters 579(2005)1715-1722,-0001,():
-1年11月30日
The mouse polymerase delta-interacting protein 1 gene, PDIP1, is mapped to chromosome 7F3 region, spans approximately 16.7kb, and is organized into six exons. The transcription start site (TSS) was determined to be G, corresponding to position of 162-bp upstream of the translation start codon. The promoter region was found to lack TATA box or CCAAT box, instead, a CpG island was detected surrounding TSS. The region from 162 to +114 is required for basal transcriptional regulation of mouse PDIP1 gene, contains two AP-2 and two Sp1 binding sites. The Sp1 site upstream of TSS activates, while the other Sp1 site and two AP-2 sites suppress the transcription activity of mouse PDIP1 gene.
Gene promoter, Gene trans, c, r, i, p, t, ion, PDIP1, Sp1, AP-2
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张健, Cheng-Keat Tan, ‡ Jian Zhang, § Zhao-Yan Li, ‡, ║ W. Gary Tarpley, ┴ Kathleen M. Downey, ‡, § and Antero G. So*, §
Biochemistry 1991, 30, 2651-2655,-0001,():
-1年11月30日
The DNA polymerase and RNase H activities of HIV reverse transcriptase are both essential for HIV replication. Although the two activities are both catalyzed by a single polypeptide, they are physically separate; i.e., the DNA polymerase resides in the N-terminal domain whereas the RNase H is localized in the C-terminal domain. The present study was undertaken to characterize the enzymatic properties of these two activities and to determine whether the two catalytic sites are also functionally distinct. We haveobserved that EGTA specifically stimulates, whereas CaCI2 selectively inhibits, the RNA-dependent DNA polymerase activity but that neither compound has any effect on the RNase H activity of a recombinant HIV reverse transcriptase. The stimulation of the DNA polymerase activity by EGTA is dependent on the Mg2+ concentration; the greatest stimulation is observed at low Mg2+ concentrations. Similarly, the inhibition of DNA polymerase activity by Ca2+ is influenced by Mg2+ concentration. Ca2+ inhibition can be reversed by increasing Mg2+ concentrations, suggesting the possibility that CaCI: inhibits the reverse transcriptase activity by competing for a metal-binding site on the enzyme. The pyrophosphate analogue phosphonoformate selectively inhibits the polymerase activity but not the RNase H activity of HIV reverse transcriptase. In constrast, the RNase H activity can be selectively inhibited by deoxyadenosine 5'-monophosphate, whereas the DNA polymerase activity is not inhibited. These results suggest that the DNA polymerase and RNase activities are not only physically separate but that they are also functionally distinct.
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【期刊论文】Detection of TP53 mutation using a portable surface plasmon resonance DNA-based biosensor
张健, Tieshan Jiang a, b, Maria Minunni b, *, P. Wilson c, Jian Zhang a, A.P.F. Turner c, Marco Mascini b
Biosensors and Bioelectronics 20(2005)1939-1945,-0001,():
-1年11月30日
A DNA-based surface plasmon resonance (SPR) biosensor has been developed for the detection of TP53 mutation using the inexpensive and commercially available instrument, SPREETATM SPR-EVM-BT, from Texas Instruments. A direct immobilisation procedure, based on the coupling of thiol-derivatised oligonucleotide probes (Probe-C6-SH) to bare gold sensor surfaces, was optimized using synthetic oligonucleotides. Hybridisation reactions between the immobilised probe and a short sequence (26 mer) complementary, non-complementary and one-point mutation DNA were then investigated. The main analytical parameters of the sensor system were studied in detail including selectivity, sensitivity, reproducibility and analysis time. Finally, the sensor system was successfully applied to polymerase chain reaction (PCR)-amplified real samples, DNA extracted from both normal, wild-type, (Jurkat) and mutated (Molt 4), carrying the mutation at codon 248 of the TP53 cell lines. The results obtained demonstrate that the DNA-based SPR biosensor was able to distinguish sequences present in the various samples that differ only by one base; and hence, it appears to be a strong candidate technique for the detection of gene mutation.
SPR, DNA biosensor, TP53, Mutation, SpreetaTM
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张健, JIANLIN ZHOU, XIAOXIAO HU, XIWEN XIONG, XIN LIU, YUNHAI LIU, KAIQUN REN, TIESHAN JIANG, XIANG HU, AND JIAN ZHANGn
JOURNAL OF EXPERIMENTAL ZOOLOGY 303A: 227-240 (2005),-0001,():
-1年11月30日
Human polymerase delta-interacting protein 1 (PDIP1) is a tumor necrosis factor a and interleukin 6 inducible protein that interacts directly with proliferating cell nuclear antigen (PCNA) and the small subunit (p50) of DNA polymerase d. PDIP1 binds PCNA and p50 simultaneously and stimulates polymerase d activity in vitro in the presence, but not the absence, of PCNA. It has been suggested that PDIP1 provides a link between cytokine activation and DNA replication in eukaryotes. Here these authors report the cloning of two rat genes homologous to human PDIP1, termed rat PDIP1 and rat tumor necrosis factor-induced protein 1 (TNFAIP1). The rat PDIP1 is mapped to chromosome 1q36 cM region, spans approximately 18.7 kb, and is organized into six exons. The rat TNFAIP1 gene is mapped to chromosome 10q25 cM, spans approximately 12.9 kb, and is composed of seven exons. The deduced proteins of rat PDIP1 and rat TNFAIP1 share 63.1% sequence identity with each other and are highly conserved in the majority of the middle portion of the two proteins, which encode a BTB/POZ domain at the N-terminus and a PCNA binding motif (QTKV-EFP) at the C-terminus, respectively. The BTB/POZ domain and the PCNA binding motif are highly conserved during the evolution. Both rat PDIP1 and rat TNFAIP1 were demonstrated to interact with PCNA via BIAcore, GST pull-down, and co-mmunoprecipitation assays. Like the human PDIP1, both rat PDIP1 and rat TNFAIP1 stimulate polymerase d activity in vitro in a PCNA-dependent way. J. Exp. Zool. 303A: 227-240, 2005.
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