刘耕
主要运用和通过遗传学及细胞生物学等多种手段与模式研究肿瘤抑制基因p53的作用机制及其和负向调节因子Mdm2的相互作用。
个性化签名
- 姓名:刘耕
- 目前身份:
- 担任导师情况:
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学术头衔:
博士生导师, 教育部“新世纪优秀人才支持计划”入选者
- 职称:-
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学科领域:
生物化学
- 研究兴趣:主要运用和通过遗传学及细胞生物学等多种手段与模式研究肿瘤抑制基因p53的作用机制及其和负向调节因子Mdm2的相互作用。
刘耕,教授、博士生导师。学习经历:1988年毕业于武汉大学生物系,获生物化学学士学位;1991年毕业于武汉大学生物系,获生物化学硕士学位;1999年毕业于美国德克萨斯大学健康医学中心生物医学研究生院,获博士学位。研究经历:2000-2005年于德克萨斯大学M.D.Anderson癌症中心进行博士后研究;2006-至今 南京大学模式动物研究所教授、博士生导师。
研究成果:室主要运用和通过遗传学及细胞生物学等多种手段与模式研究肿瘤抑制基因p53的作用机制及其和负向调节因子Mdm2的相互作用。已取得的主要学术成果包括:1)通过“基因敲入”手段建立含有不同p53突变的小鼠模型,发现了p53突变体与肿瘤转移的联系,并建立了包含不同p53突变的小鼠肿瘤模型。2)通过研究p53所激活的几种不同的下游通路在肿瘤抑制中的作用与贡献,首次用体内研究明确地证实了p53控制细胞周期和染色体稳定性在其肿瘤抑制功能中的重要性。3)发现了p53-Mdm2轴心在小鼠发育及多种组织中的保护和监控机制。
承担项目:国家重大科技研究计划(973项目)《心脏发育与血管发生过程中的信号调控机制研究》(2006-2011)课题二 负责人;国家自然科学基金项目 《建立激活肿瘤抑制机制进行癌症预防的小鼠模型研究》 (2008-2010)课题负责人;国家自然科学基金项目 《p53下游新通路的功能研究》 (2009-2011)课题负责人;教育部新世纪优秀人才资助计划 《p53肿瘤抑制机制及调控》(2008-2010):课题负责人。
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【期刊论文】p21 delays tumor onset by preservationof chromosomal stability
刘耕, Juan A. Barboza*†, Geng Liu*, Zhenlin Ju*‡, Adel K. El-Naggar§, and Guillermina Lozano*†¶
19842-19847, PNAS, December 26, 2006, vol. 103, no.52,-0001,():
-1年11月30日
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刘耕, Geng Liu, John M Parant, Gene Lang, Patty Chau, Arturo Chavez-Reyes, Adel K El-Naggar, Asha Multani, Sandy Chang & Guillermina Lozano
NATURE GENETICS VOLUME 36, NUMBER 1, JANUARY 2004,-0001,():
-1年11月30日
The p53 protein integrates multiple upstream signals andfunctions as a tumor suppressor by activating distinctdownstream genes1–3. At the cellular level, p53 inducesapoptosis, cell cycle arrest and senescence. A rare mutant formof p53 with the amino acid substitution R175P, found in humantumors, is completely defective in initiating apoptosis butstill induces cell cycle arrest4,5. To decipher the functionalimportance of these pathways in spontaneous tumorigenesis,we used homologous recombination to generate mice withmutant p53-R172P (the mouse equivalent of R175P in humans).Mice inheriting two copies of this mutation (Trp53515C/515C)escape the early onset of thymic lymphomas that characterizeTrp53-null mice. At 7 months of age, 90% of Trp53-null micehad died, but 85% of Trp53515C/515C mice were alive andtumor-free, indicating that p53-dependent apoptosis was notrequired for suppression of early onset of spontaneous tumors.The lymphomas and sarcomas that eventually developed inTrp53515C/515C mice retained a diploid chromosome number, insharp contrast to aneuploidy observed in tumors and cells fromTrp53-null mice. The ability of mutant p53-R172P to induce apartial cell cycle arrest and retain chromosome stability arecrucial for suppression of early onset tumorigenesis.
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【期刊论文】Synergistic roles of Mdm2 and Mdm4 for p53inhibition in central nervous system development
刘耕, Shunbin Xiong*, Carolyn S. Van Pelt†, Ana C. Elizondo-Fraire*, Geng Liu*, and Guillermina Lozano*‡
3226-3231, PNAS, February 28, 2006, vol. 103, no.9,-0001,():
-1年11月30日
Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that arep53-dependent. To determine whether Mdm2 and Mdm4 inhibitp53 function redundantly in a more restricted cell type, conditionalalleles were crossed to a neuronal specific Cre transgene to deleteMdm2 and Mdm4 in the CNS. Mice lacking Mdm2 in the CNSdeveloped hydranencephaly at embryonic day 12.5 due to apoptosis,whereas Mdm4 deletion showed a proencephaly phenotypeat embryonic day 17.5 because of cell cycle arrest andapoptosis. The deletion of both genes, strikingly, contributed to aneven earlier and more severe CNS phenotype. Additionally, Mdm2and Mdm4 had a gene dosage effect, because loss of three of thefour Mdm alleles also showed a more accelerated CNS phenotypethan deletion of either gene alone. All phenotypes were rescued bydeletion of p53. Thus, these in vivo data demonstrate the importanceof Mdm4 independent of Mdm2 in inhibition of p53
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【期刊论文】p21 stability: Linking chaperones to a cell cycle checkpoint
刘耕, Geng Liu and Guillermina Lozano*
CANCER CELL: FEBRUARY 2005, VOL. 7,-0001,():
-1年11月30日
Progression through the cell cycle is regulated by numerous proteins, one of which is the cyclin-dependent kinase inhibitor, p21. A new study identifies a novel protein complex that stabilizes p21. The stability of this complex is critical in effecting the p53-mediated cell cycle checkpoint.
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【期刊论文】Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome
刘耕, Gene A. Lang, , Tomoo Iwakuma, Young-Ah Suh, Geng Liu, V. Ashutosh Rao, John M. Parant, Yasmine A. Valentin-Vega, Tamara Terzian, Lisa C. Caldwell, Louise C. Strong, Adel K. EI-Naggar, and Gullermlna Lozano, *
Cell, Vol. 119, 861-872, December 17, 2004, Copyright,-0001,():
-1年11月30日
negaIndividualswith Li-Fraumeni syndrome carry inherited tive p53 mutants can inhibit the function of the normalmutations in the p53 tumor suppressor gene and are p53 protein, usually through protein-protein interactionspredisposed to tumor development. To examine the (Milner et al., 1991). The dominant-negative hypothesismechanistic nature of these p53 missense mutations, is strongly supported by the observations that manywe generated mice harboring a G-to-A substitution at mutant p53 proteins have an increased half-life (Finlaynucleotide 515 of p53 (p53_/515A) corresponding to the et al., 1988; Hinds et al., 1990; Slingerland et al., 1993)p53R175H hot spot mutation in human cancers. Al- and that they oligomerize with wild-type p53, inhibitingthough p53_/515Amice display a similar tumor spectrum its function (Farmer et al., 1992; Jeffrey et al., 1995;and survival curve as p53_/_mice, tumors fromp53_/515A Milner et al., 1991; Sturzbecher et al., 1992). The formamicemetastasized with high frequency. Correspond- tion of mixed wild-type and mutant p53 molecules coningly,the embryonic fibroblasts from the p53515A/515A verts wild-type p53 into themutant conformation in vitromutant mice displayed enhanced cell proliferation, (Milner et al., 1991). Gain-of-function mutations, on theDNA synthesis, and transformation potential. The dis- other hand, are those missense mutations in which muruptionof p63 and p73 in p53_/_ cells increased trans- tant p53 has additional functions not seen in wild-typeformation capacity and reinitiated DNA synthesis to p53. For example, the p53R175H mutant, when overexlevelsobserved in p53515A/515A cells. Additionally, p63 pressed in a nontransformed cell line lacking p53, yieldsand p73 were functionally inactivated in p53515A cells. tumors in nude mice, while the parental cell line doesThese results provide in vivo validation for the gain-of- not (Dittmer et al., 1993). Transgenic mice overexpressfunctionproperties of certain p53missensemutations ing the human p53R175H mutation in epithelial cellsand suggest a mechanistic basis for these pheno- exhibit an increased susceptibility to chemical carcinotypes.
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【期刊论文】High metastatic potential in mice inheriting a targeted p53 missense mutation
刘耕, Geng Liu*, Timothy J. McDonnell†, Roberto Montes de Oca Luna*‡, Mini Kapoor*, Betsy Mims*, Adel K. El-Naggar§, and Guillermina Lozano*¶
4174-4179, PNAS, April 11, 2000, vol. 97, no.8,-0001,():
-1年11月30日
To understand the relevance of p53 missense mutations in vivo, we generated a mouse containing an arg-to-his substitution at p53 amino acid 172, which corresponds to the R175H hot-spot mutation in human tumors by homologous recombination. Inadvertently, this mouse contains the additional deletion of a G nucleotide at a splice junction that attenuates levels of mutant p53 to near wild-type levels. Mice heterozygous for the mutant allele differed from p53___ mice in tumor spectrum, with a significant increase in the number of carcinomas and a slight decrease in the number of lymphomas. More importantly, the osteosarcomas and carcinomas that developed in these mutant mice frequently metastasized (69% and 40%, respectively). In contrast, metastasis is rare in osteosarcomas of p53___ mice. Loss of heterozygosity studies of tumors indicated loss of heterozygosity in only 1 of 11 tumors. These data indicate clear differences between a p53 missense mutation and a null allele in tumorigenesis in vivo and suggest that the p53R172H_g mutant represents a gain-of-function allele.
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【期刊论文】Mouse models dissect the role of p53 in cancer anddevelopment
刘耕, Guillermina LozanoU and Geng Liu
seminars in CANCER BIOLOGY, Vol 8, 1998: pp. 337-344,-0001,():
-1年11月30日
Mice lacking one or two copies of the p53 gene haveprovided invaluable insight into the process of tumorigenesis.The importance of apoptosis in suppression of tumorigenesisin vivo became evident from analysis of these mice.Moreover, the timing and kinds of tumors that develop inthese mice are altered by the presence of additional inheritedmutations, by strain differences, and by food intake. Developmentalabnormalities are also visible in mice with loss ofp53 and with overexpression of p53 suggesting that p53levels are critical for normal cellular processes. While mice donot necessarily recapitulate all the tumor types found ininherited cancers, they offer the unique opportunity to decipherthe critical pathways in tumorigenesis. These findingscan then be applied to humans.
tumor modelsr/, p53 rnull mice/, genetic interactionsr/, development
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【期刊论文】Mutation of Phosphoserine 389 Affects p53 Function in Vivo*
刘耕, Mingming Hao‡, Andrew M. Lowy§, Mini Kapoor, Abdul Deffie¶, Geng Liu, andGuillermina Lozanoi
THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 271, No.46, Issue of November 15, pp. 29380-29385, 1996,-0001,():
-1年11月30日
To study the importance of phosphorylation for p53transactivation function, we generated mutations ateach of its known phosphorylated serine amino acids.Mutations of murine p53 serine residues individually toeither alanine or glutamic acid at positions 7, 9, 12, 18,37, 312, and 389 resulted in equivalent levels of transcriptionalactivation in standard transient transfectionexperiments. However, when p53 transcriptional activitywas measured in cells that attain G1 arrest uponcontact inhibition, wild-type p53 was inactive, and onlyalteration at serine 389 to glutamic acid resulted in afunctional p53 protein. This Ser 3 Glu mutant also hasan increased ability to bind DNA. Elimination of thephosphorylation site by substitution of an alanineamino acid resulted in loss of transcriptional activity.We also demonstrated that specific phosphorylation ofp53 at serine 389 is induced by cyclin E overexpressionin high-density cells. Our data establish for the first timethat phosphorylation of p53 at serine 389 is important inactivating its function in vivo.
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