李珍
遗传学,分子生物学,细胞生物学和分子神经学等领域
个性化签名
- 姓名:李珍
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学术头衔:
博士生导师
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学科领域:
生物化学
- 研究兴趣:遗传学,分子生物学,细胞生物学和分子神经学等领域
李珍,博士,清华大学生物科学与技术系副教授。1988年毕业于武汉大学生物系,同年参加中美联合CUSBEA项目考试,以分子生物学考分第一的优异成绩被选拔赴美留学,就读于位于宾西法尼亚州匹茲堡市的卡内基-梅隆大学 (Carnegie Mellon University)。攻读博士生期间成绩卓著,曾多次在国际学术会议上做学术报告,介绍自己的研究工作,并且发表了两篇高质量的学术论文,颇受导师们的赞赏。1995年获得生物学博士学位。 1995-1997年在美国密西根大学(University of Michigan)医学院从事博士后研究,从师于著名爱滋病研究专家Gary Nabel教授,克隆了一个新的I?B 基因,被命名为I?B-?。 1997-1999年在美国斯坦福大学(Stanford University)Richard Myers教授实验室继续从事博士后研究,利用果蝇作为模型生物来探索人类遗传病Huntington’s disease (HD)的发病机制, 克隆了果蝇的HD基因,并对其功能进行了系统的研究,为Huntington’s disease的研究作出了贡献。2000年起在香港科技大学生物化学系担任研究员,期间主持并参与了一个重大项目的研究工作,取得了突破性的进展,开创了一个研究Cdk5蛋白激酶作用的新领域,在国际上居领先水平。
2004 年7月正式受聘于清华大学生物科学与技术系,为本系本科生讲授生物化学。此课为校级精品课,完全用英文讲授。对待教学工作认真负责,并注重教书育人,成为学生们喜爱的老师,讲课也受到了学生们的一致好评。经过多年在国外的学习和工作,积累了丰富的研究经验,发表学术论文多篇,研究涉及遗传学,分子生物学,细胞生物学和分子神经学等领域。目前承担国家自然科学基金课题,研究领域包括蛋白质分子之间的相互作用与功能,真核生物基因表达的调控以及人类遗传病的分子机制。
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2146
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405
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成果数
7
李珍, Peggy F. Shelbourne, , *, Nigel Killeen, Robert F. Hevner, Heather M. Johnston, Laurence Tecott, Mark Lewandoski, Margaret Ennis, Lucia Ramirez, Zhen Li, Carlo Iannicola, +, Dan R. Littman and Richard M. Myers
Human Molecular Genetics, 1999, Vol. 8, No.5 763-774,-0001,():
-1年11月30日
Huntington's disease (HD) is a dominant disorder characterized by premature and progressive neurodegeneration. In order to generate an accurate model of the disease, we introduced an HD-like mutation (an extended stretch of 72–80 CAG repeats) into the endogenous mouse Hdh gene. Analysis of the mutation in vivo reveals significant levels of germline instability, with expansions, contractions and sex-of-origin effects in evidence. Mice expressing full-length mutant protein display abnormal social behaviour in the absence of acute neurodegeneration. Given that psychiatric changes, including irritability and aggression, are common findings in HD patients, our data are consistent with the hypothesis that some clinical features of HD may be caused by pathological processes that precede gross neuronal cell death. This implies that effective treatment of HD may require an understanding and amelioration of these dysfunctional processes, rather than simply preventing the premature death of neurons in the brain. These mice should facilitate the investigation of the molecular mechanisms that underpin the pathway from genotype to phenotype in HD.
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李珍, Amanda G. Paulovich, J. Ryan Thompson, John C. Larkin, s Zhen Li and John L. Woolford, Jr.
Genetics 135: 719-730 (November, 1999),-0001,():
-1年11月30日
The Saccharomyces cerevisiae CRY1 gene encodes the 40S ribosomal subunit protein rp59 and confers sensitivity to the protein synthesis inhibitor cryptopleurine. A yeast strain containing the cryl-AI::URA3 null allele is viable, cryptopleurine sensitive (CryS), and expresses rp59 mRNA, suggesting that there is a second functional CRY gene. The CRY2 gene has been isolated from a yeast genomic library cloned in bacteriophage; using a CRY1 DNA probe. The DNA sequence of the CRY2 gene contains an open reading frame encoding ribosomal protein 59 that differs at five residues from rp59 encoded by the CRY1 gene. The CRY2 gene was mapped to the left arm of chromosome X, centromere- proximal to cdc6 and immediately adjacent to ribosomal protein genes RPS24A and RPL46. Ribosomal protein 59 is an essential protein; upon sporulation of a diploid doubly heterozygous for cryl-A2::TRP1 cry2-AI::LEU2 null alleles, no spore clones containing both null alleles were recovered. Several results indicate that CRY2 is expressed, but at lower levels than CRYI: (1) Introduction of CRY2 on high copy plasmids into CryR yeast of genotype cry1 CRY2 confers a Crys phenotype. Transformation of these CryR yeast with CRY2 on a low copy CEN plasmid does not confer a Crys phenotype. (2) Haploids containing the cryl-A2::TRP1 null allele have a deficit of 40S ribosomal subunits, but cry2-AI::LEU2 strains have wild-type amounts of 40S ribosomal subunits. (3) CRY2 mRNA is present at lower levels than CRY1 mRNA. (4) Higher levels of 13-galactosidase are expressed from a CRYI-lacZ gene fusion than from a CRY2-1acZ gene fusion. Mutations that alter or eliminate the last amino acid of rp59 encoded by either CRY1 or CRY2 result in resistance to cryptopleurine. Because CRY2 (and cry2) is expressed at lower levels than CRY1 (and cryl), the CryR phenotype of cry2 mutants is only expressed in strains containing a cryl-A null allele.
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【期刊论文】Pctaire1 Interacts with p35 and Is a Novel Substrate for Cdk5/p35*
李珍, Kai Cheng‡, Zhen Li‡, Wing-Yu Fu, Jerry H. Wang, Amy K. Y. Fu, and Nancy Y. Ip§
Vol. 277, No.35, Issue of August 30, pp. 31988-31993, 2002,-0001,():
-1年11月30日
Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that plays important roles during central nervous system development. Cdk5 kinase activity depends on its regulatory partners, p35 or p39, which are prominently expressed in the central nervous system. We have previously demonstrated the involvement of Cdk5 in the regulation of acetylcholine receptor expression at the neuromuscular junction, suggesting a novel functional role of Cdk5 at the synapse. Here we report the identification of Pctaire1, a member of the Cdkrelated kinase family, as a p35-interacting protein in muscle. Binding of Pctaire1 to p35 can be demonstrated by in vitro binding assay and co-immunoprecipitation experiments. Pctaire1 is associated with p35 in cultured myotubes and skeletal muscle, and is concentrated at the neuromuscular junction. Furthermore, Pctaire1 can be phosphorylated by the Cdk5/p25 complex, and serine 95 is the major phosphorylation site. In brain and muscle of Cdk5 null mice, Pctaire1 activity is significantly reduced. Moreover, Pctaire1 activity is increased following preincubation with brain extracts and phosphorylation by the Cdk5/p25 complex. Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity.
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【期刊论文】A putative Drosophila homolog of the Huntington's disease gene
李珍, Zhen Li+, Chris A. Karlovich+, Matthew P. Fish, Matthew P. cott and Richard M. Myers
Human Molecular Genetics, 1999, Vol. 8, No.9 1807-1815,-0001,():
-1年11月30日
The Huntington's disease (HD) gene encodes a protein, huntingtin, with no known function and no detectable sequence similarity to other proteins in current databases. To gain insight into the normal biological role of huntingtin,we isolated and sequenced a cDNAencoding a protein that is a likely homolog of theHD gene product in Drosophila melanogaster. We also determined the complete sequence of 43 125 contiguous base pairs of genomic DNA that encompass the Drosophila HD gene, allowing the intron-exon structure and 5'- and 3'-flanking regions to be delineated. The predicted Drosophila huntingtin protein has 3583 amino acids, which is several hundred amino acids larger than any other previously characterized member of the HDfamily. Analysis of the genomic and cDNA sequences indicates that Drosophila HD has 29 exons, compared with the 67 exons present in vertebrate HD genes, and that Drosophila huntingtin lacks the polyglutamine and polyproline stretches present in its mammalian counterparts. TheDrosophila HD mRNA is expressed in a broad range of developmental stages and in the adult, a temporal pattern of expression similar to that observed for mammalian HD transcripts. We can discern five regions of high similarity from multiple sequence alignments between Drosophila and vertebrate huntingtins. These regions may define functionally important domains within the protein.
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【期刊论文】Cdk5/p35 Phosphorylates mSds3 and Regulates mSds3-mediated Repression of Transcription*
李珍, Zhen Li‡§, Gregory David¶, Kwok-Wang Hung‡, Ronald A. DePinho¶**, Amy K. Y. Fu‡, and Nancy Y. Ip‡ ‡‡
Vol. 279, No.52, Issue of December 24, pp. 54438-54444, 2004,-0001,():
-1年11月30日
Cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase that displays kinase activity predominantly in neurons, is activated by two non-cyclin activators, p35 or p39. Here, we report a physical and functional interaction between the Cdk5/p35 complex and mouse Sds3 (mSds3), an essential component of mSin3-histone deacetylase (HDAC) co-repressor complex. mSds3 binds to p35 both in vitro and in vivo, enabling active Cdk5 to phosphorylate mSds3 at serine 228. A mSds3 S228A mutant retained mSin3 binding activity, but its dimerization was not greatly enhanced by p35 when compared with wild type. Notably, p35 overexpression augmented mSds3-mediated transcriptional repression in vitro. Interestingly, mutational studies revealed that the ability of exogenous mSds3 to rescue cell growth and viability in mSds3 null cells correlates with its ability to be phosphorylated by Cdk5. The identification of mSds3 as a substrate of the Cdk5/p35 complex reveals a new regulatory mechanism in controlling the mSin3-HDAC transcriptional repressor activity and provides a new potential therapeutic means to inhibit specific HDAC activities in disease.
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李珍, ZHEN LI, AMANDA G. PAULOVICH, † AND JOHN L. WOOLFORD, JR.*
MOLECULAR AND CELLULAR BIOLOGY, Nov. 1995, p. 6454-6464,-0001,():
-1年11月30日
The Saccharomyces cerevisiae CRY1 and CRY2 genes, which encode ribosomal protein rp59, are expressed at a 10:1 ratio in wild-type cells. Deletion or inactivation of CRY1 leads to 5- to 10-fold-increased levels of CRY2 mRNA. Ribosomal protein 59, expressed from either CRY1 or CRY2, represses expression of CRY2 but not CRY1. cis-Acting elements involved in repression of CRY2 were identified by assaying the expression of CRY2-lacZ gene fusions and promoter fusions in CRY1 CRY2 and cry1-D CRY2 strains. Sequences necessary and sufficient for regulation lie within the transcribed region of CRY2, including the 5* exon and the first 62 nucleotides of the intron. Analysis of CRY2 point mutations corroborates these results and indicates that both the secondary structure and sequence of the regulatory region of CRY2 pre-mRNA are necessary for repression. The regulatory sequence of CRY2 is phylogenetically conserved; a very similar sequence is present in the 5* end of the RP59 gene of the yeast Kluyveromyces lactis. Wild-type cells contain very low levels of both CRY2 pre-mRNA and CRY2 mRNA. Increased levels of CRY2 pre-mRNA are present in mtr mutants, defective in mRNA transport, and in upf1 mutants, defective in degradation of cytoplasmic RNA, suggesting that in wild-type repressed cells, unspliced CRY2 pre-mRNA is degraded in the cytoplasm. Taken together, these results suggest that feedback regulation of CRY2 occurs posttranscriptionally. A model for coupling ribosome assembly and regulation of ribosomal protein gene expression is proposed.
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【期刊论文】A New Member of the IkB Protein Family, IkBe, Inhibits RelA (p65)-Mediated NF-kB Transcription
李珍, ZHEN LI AND GARY J. NABEL*
MOLECULAR AND CELLULAR BIOLOGY, Oct. 1997, p. 6184-6190,-0001,():
-1年11月30日
A novel member of the IkB family has been identified as a protein that associated with the p50 subunit of NF-kB in a yeast two-hybrid screen. Similar to previously known IkB proteins, this member, IkB
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