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페이스북 트위터 카카오톡 네이버밴드 링크복사

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자연과학 >생물ㆍ화학ㆍ환경 >생물학
강의학기

2012년 2학기

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An overview of cell signaling pathways with emphasis on the relationship of function and disease association. In addition to regular classes, two students/each week (~15min/student) will have meetings with a course director to get comments for references described in course syllabus.

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PI3 kinase-Function analisis of p110 mutations

차시별 강의

1.	PI3 kinase-Function analisis of p110 mutations	● Functional Analysis of PIK3CA Gene Mutations in Human Colorectal Cancer [Ikenoue T et al. Cancer Res 65:4562 (2005)]. ● Cancer-associated p110a mutantions induce a gain of function in p110a (the kinase activity is significantly upregulated). ● Based on -In vitro PI3K assay -Immunoblot for phosphorylation of well-defined downstream molecules, such as Akt and p70S6K -Transformation assay
	PI3 kinase-Mechanism of cancer-associated mutations	● Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit [Miled N. et al Science 317:239 (2007)]. ● Oncogenic mutations in the ABD are not in the interface with the p85 regulatory subunit. ● p85 inhibition of p110a occurs though a charge-charge interaction between p110a helical domain and p85ni [p110a helical domain oncogenic mutation (such as E545K) disrupts an inhibitory charge-charge interaction with the p85 nSH2]. ● Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers [Engelman JA et al. Nat Medicine 14:1351 (2008)]. ● A mouse model of lung adenocarcinomas initiated and maintained by expression of p110-a H1047R. ● Treatment of these tumors with NVP-BEZ235, a dual pan–PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression.
2.	SAPK-p38α null mice	● p38a MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation [Ventura JJ et al. Nat Genet. 39:750 (2007)]. ● p38a positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation. ● p38a controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor. ● Inactivation of p38a leads to an immature and hyperproliferative lung epithelium that is highly sensitized to K-RasG12V-induced tumorigenesis. ● p38a has a key role in the regulation of lung cell renewal and tumorigenesis.
	SAPK-p38α null mice	● p38a MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation [Ventura JJ et al. Nat Genet. 39:750 (2007)]. ● p38a positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation. ● p38a controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor. ● Inactivation of p38a leads to an immature and hyperproliferative lung epithelium that is highly sensitized to K-RasG12V-induced tumorigenesis. ● p38a has a key role in the regulation of lung cell renewal and tumorigenesis.
	SAPK-p38δ null mice	● Regulation of PKD by the MAPK p38d in Insulin Secretion and Glucose Homeostasis [Sumara G et al. Cell 136:235 (2009)]. ● p38δ null mice display improved glucose tolerance due to enhanced insulin secretion from pancreatic B cells. ● Deletion of p38d results in pronounced activation of protein kinase D (PKD), a pivotal regulator of stimulated insulin exocytosis. p38d catalyzes an inhibitory phosphorylation of PKD1, thereby attenuating stimulated insulin secretion. ● p38d null mice are protected against high-fat-feedinginduced insulin resistance and oxidative stressmediated B cell failure. ● p38d-PKD pathway integrates regulation of the insulin secretory capacity and survival of pancreatic B cells, pointing to a pivotal role for this pathway in the development of overt diabetes mellitus.
	SAPK-p38δ null mice	● Regulation of PKD by the MAPK p38d in Insulin Secretion and Glucose Homeostasis [Sumara G et al. Cell 136:235 (2009)]. ● p38δ null mice display improved glucose tolerance due to enhanced insulin secretion from pancreatic B cells. ● Deletion of p38d results in pronounced activation of protein kinase D (PKD), a pivotal regulator of stimulated insulin exocytosis. p38d catalyzes an inhibitory phosphorylation of PKD1, thereby attenuating stimulated insulin secretion. ● p38d null mice are protected against high-fat-feedinginduced insulin resistance and oxidative stressmediated B cell failure. ● p38d-PKD pathway integrates regulation of the insulin secretory capacity and survival of pancreatic B cells, pointing to a pivotal role for this pathway in the development of overt diabetes mellitus.
3.	14-3-3 protein-zeta	● 14-3-3ζ Overexpression Defines High Risk for Breast Cancer Recurrence and Promotes Cancer Cell Survival [Neal CL et al. Cancer Res. 69:3425 (2009)]. ● 14-3-3ζ is overexpressed in >40% of advanced stage breast cancers and is correlated with poor survival in breast cancer patients. ● 14-3-3ζ overexpression confers cancer cell apoptosis resistance. Increased ● 14-3-3Z expression enhanced anchorage-independent growth and inhibited stress-induced apoptosis, whereas downregulation of 14-3-3Z reduced anchorage-independent growth and sensitized cells to stress-induced apoptosis via the mitochondrial apoptotic pathway. ● Overexpression of 14-3-3zeta in cancer cells activates PI3K via binding the p85 regulatory subunit [Neal CL et al. Oncogene Jul 11 (2011)]. ● 14-3-3 zeta bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. ● A single 14-3-3-binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3 zeta-mediated p85 binding and PI3K/Akt activation.
	14-3-3 protein-sigma	● 14-3-3σ controls mitotic translation to facilitate cytokinesis [Wilker EW et al. Nature 446:329 (2007)]. ● 14-3-3s as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B. ● Cells lacking 14-3-3s cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. ● This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells.
	14-3-3 protein-sigma	● 14-3-3σ controls mitotic translation to facilitate cytokinesis [Wilker EW et al. Nature 446:329 (2007)]. ● 14-3-3s as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B. ● Cells lacking 14-3-3s cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. ● This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells.
4.	CDC25 Phosphatases-Oncogenes	● CDC25 Phosphatases as Potential Human Oncogenes [Galktionov K et al. Science 269:1575 (1995)] ● Cyclin-dependent kinases (CDKs) are activated by CDC25 phosphatases, which remove inhibitory phosphate from tyrosine and threonine residues. ● In rodent cells, human CDC25A or CDC25B but not CDC25C phosphatases cooperate with either Ha-RASGl2v or loss of RB1 in oncogenic focus formation. ● Such transformants were highly aneuploid, grew in soft agar, and formed high-grade tumors in nude mice. ● Overexpression of CDC25B was detected in 32 percent of human primary breast cancers tested. ● The CDC25 phosphatases may contribute to the development of human cancer.
	CDC25A Phosphatase-Overexpression in mice	● Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability [Ray D et al. Cancer Res 67:984 (2007)] ● Transgenic expression of CDC25A cooperates markedly with oncogenic ras or neu in murine mammary tumorigenesis. ● MMTV-CDC25A transgenic mice exhibit alveolar hyperplasia in the mammary tissue but do not develop spontaneous mammary tumors. ● The MMTVCDC25A transgene markedly shortens latency of tumorigenesis in MMTV-ras mice. ●The MMTV-CDC25A transgene also accelerates tumor growth inMMTV-neu mice with apparent cell cycle miscoordination. ●The MMTV-CDC25A transgene also accelerates tumor growth inMMTV-neu mice with apparent cell cycle miscoordination. ● CDC25A-overexpressing tumors, which invade more aggressively, exhibit various chromosomal aberrations on fragile regions. ● The chromosomal aberrations account for substantial changes in gene expression profile rendered by transgenic expression of CDC25A, including down-regulation of Trp73. ● Deregulated control of cellular CDC25A levels leads to in vivo genomic instability, which cooperates with the neu-ras oncogenic pathway in mammary tumorigenesis. ● Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A [Pereg Y et al. Nat Cell Biol 12:400 (2010)]. ● Cdc25A is stabilized by the ubiquitin hydrolase Dub3. ● Upon binding Cdc25A, Dub3 removes the polyubiquitin modifications that mark Cdc25A for proteasomal degradation. ● Dub3 overexpression is responsible for an abnormally high level of Cdc25A in a subset of human breast cancers. ● Dub3 knockdown significantly retarded the growth of breast tumour xenografts in nude mice.
5.	CDK4 R24C transgenic mice	● Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors [Sotillo R et al. EMBO J 20:6637 (2001)] ● primary embryonic fibroblasts expressing the mutant Cdk4R24C kinase are immortal and susceptible to transformation by Ras oncogenes. ● Homozygous Cdk4R24C/R24C mutant mice develop multiple tumors with almost complete penetrance. ● Cdk4 R24C cooperates with p53 and p27Kip1 deficiencies in decreasing tumor latency and favoring development of speci®c tumor types.
	CDK4 R24C transgenic mice-Flavopiridol treatment	● Cooperation between Cdk4 and p27kip1 in Tumor Development: A Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity [Sotillo R et al. Cancer Res 65:3846 (2005)] ● Exposure to flavopiridol, a wide-spectrum Cdk inhibitor, significantly delays tumor progression and leads to tumorfree survival in a significant percentage of treated Cdk4 R24C mice. ● genetically engineered tumor models involving key cell cycle regulators are a valuable tool to evaluate drugs with potential therapeutic benefit in human cancer.
	CDK4 R24C transgenic mice-Flavopiridol treatment	● Cooperation between Cdk4 and p27kip1 in Tumor Development: A Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity [Sotillo R et al. Cancer Res 65:3846 (2005)] ● Exposure to flavopiridol, a wide-spectrum Cdk inhibitor, significantly delays tumor progression and leads to tumorfree survival in a significant percentage of treated Cdk4 R24C mice. ● genetically engineered tumor models involving key cell cycle regulators are a valuable tool to evaluate drugs with potential therapeutic benefit in human cancer.
6.	NFkB: NEMO-null mice	● Epithelial NEMO links innate immunity to chronic intestinal inflammation [Nenci A et al. Nature 446:557 (2007)] ● Intestinal epithelial-cell-specific inhibition of NF-kB through conditional ablation of NEMO spontaneously caused severe chronic intestinal inflammation in mice. ● NF-kB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. ● This epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. ● A primary NF-kB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype.
	NFkB: IKKB-null mice	● IKKB Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer [Greten FR et al. Cell 118: 285 (2004)] ● The ability of NF-B to be activated by proinflammatory stimuli and in turn inhibit apoptosis led to propose that the canonical IKK-NF-B pathway may provide the critical mechanistic link between inflammation and cancer. ● Examined whether tissue-specific deletion of IKK in the two cell types where NF-B is activated during colitis and colitis-associated cancer (CAC), could prevent tumor initiation and progression in a mouse model of CAC. ● Inactivation of IKKB in either cell type can indeed reduce the incidence and development of inflammation-associated cancer, but in each cell type IKK acts through a different mechanism. While in enterocytes IKK contributes to tumor initiation and promotion by suppressing apoptosis, but is not required for inflammation per se, in myeloid cells it is involved in production of inflammatory mediators that promote tumor growth.
7.	p53-Arginine methylation	● Arginine methylation regulates the p53 response [Jasson M et al. Nat Cell Biol. 10:1431 (2008)] ● Protein arginine methyltransferase (PRMT) 5, as a co-factor in a DNA damage responsive co-activator complex that interacts with p53, is responsible for methylating p53. ● Arginine methylation is regulated during the p53 response and affects the target gene specificity of p53. ● PRMT5 depletion triggers p53-dependent apoptosis.
	p53 variants-p53P72, p53R72	● The codon 72 polymorphic variants of p53 have markedly different apoptotic potential [Dumont P et al. Nat Genet. 33:357 (2003)] ● The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. ● In cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. ● At least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. ● The two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.
8.	BCL2 family proteins	● BCL-2, BCL-XL Sequester BH3 Domain-Only Molecules Preventing BAX- and BAK-Mediated Mitochondrial Apoptosis [Emily HY et al. Mol Cell 8:705 (2001)] ● Cells deficient for the down-stream effectors Apaf-1, Caspase-9, or Caspase-3 display only transient protection from “BH3 domain-only” molecules and die a caspase-independent death by promitochondrial dysfunction. ● Cells with an upstream defect, lacking “multidomain” BAX, BAK demonstrate long-term resistance to all BH3 domain-only members, including BAD, BIM, and NOXA. Comparison of wild-type versus mutant BCL-2, BCL-XL indicates these antiapoptotics sequester BH3 domain-only molacecules in stable mitochondrial complexes, preventing the activation of BAX, BAK. ● BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.
	BCL2 family proteins	● BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program [Ren D et al. Science 330:1390 (2010)] ● Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. ● Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c–mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. ● Thus, many forms of apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.
9.	Wnt-B-Catenin: Activation of b-Catenin–Tcf Signaling in Colon Cancer	● Activation of b-Catenin–Tcf Signaling in Colon Cancer by Mutations in b-Catenin or APC [Morin PJ et al. Science 275:1787 (1997)] ● Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. ● One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by b-catenin and T cell transcription factor 4 ( Tcf-4). ● The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. ● Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of b-catenin that altered functionally significant phosphorylation sites. ● These results indicate that regulation of b-catenin is critical to APC’s tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or b-catenin.
	Wnt-B-Catenin: Wnt5a signaling in metastatic melanoma	● Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma [Weeraratna AT et al. Cancer Cell 1:279 (2002)] ● Gene expression profiling identified human melanoma cells demonstrating increased cell motility and invasiveness. The gene WNT5A best determined in vitro invasive behavior. ● Melanoma cells were transfected with vectors constitutively overexpressing Wnt5a. Consistent changes included actin reorganization and increased cell adhesion. No increase in B-catenin expression or nuclear translocation was observed. ● There was, however, a dramatic increase in activated PKC. In direct correlation with Wnt5a expression and PKC activation, there was an increase in melanoma cell invasion. ● Blocking this pathway using antibodies to Frizzled-5, the receptor for Wnt5a, inhibited PKC activity and cellular invasion. Furthermore, Wnt5a expression in human melanoma biopsies directly correlated to increasing tumor grade.
	Wnt-B-Catenin: Wnt5a signaling in metastatic melanoma	● Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma [Weeraratna AT et al. Cancer Cell 1:279 (2002)] ● Gene expression profiling identified human melanoma cells demonstrating increased cell motility and invasiveness. The gene WNT5A best determined in vitro invasive behavior. ● Melanoma cells were transfected with vectors constitutively overexpressing Wnt5a. Consistent changes included actin reorganization and increased cell adhesion. No increase in B-catenin expression or nuclear translocation was observed. ● There was, however, a dramatic increase in activated PKC. In direct correlation with Wnt5a expression and PKC activation, there was an increase in melanoma cell invasion. ● Blocking this pathway using antibodies to Frizzled-5, the receptor for Wnt5a, inhibited PKC activity and cellular invasion. Furthermore, Wnt5a expression in human melanoma biopsies directly correlated to increasing tumor grade.
10.	JAK-STAT: JAK2 V617F mutation in polycythaemia vera	● A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera [James C et al. Nature 434:1144 (2005)] ● Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. ● A constitutive tyrosine kinase activity could be at the origin of these diseases. ● A clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (>80%) polycythaemia vera patients. ● JAK2 V617F mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.
	JAK-STAT: JAK2 Exon 12 Mutations in Myeloproliferative disorders	● JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis [Scott LM et al. N Engl J Med 356:459 (2007)] ● JAK2 V617F mutation is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear. ● We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. ● The mutations resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation. ● JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis.
	JAK-STAT: JAK2 Exon 12 Mutations in Myeloproliferative disorders	● JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis [Scott LM et al. N Engl J Med 356:459 (2007)] ● JAK2 V617F mutation is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear. ● We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. ● The mutations resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation. ● JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis.
11.	Ubiquitination: HDM2 inhibitor	● Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells [Yang et al. Cancer Cell 7:547 (2005)] ● The p53 tumor suppressor protein is regulated by its interaction with HDM2, which serves as a ubiquitin ligase (E3) to target p53 for degradation. ● We have identified a family of small molecules (HLI98) that inhibits HDM2’s E3 activity. These compounds show some specificity for HDM2 in vitro. ● In cells, the compounds allow the stabilization of p53 and HDM2 and activation of p53-dependent transcription and apoptosis.
	Ubiquitination: Cullin3-caspase 8 Ub	● Cullin3-Based Polyubiquitination and p62-Dependent Aggregation of Caspase-8 Mediate Extrinsic Apoptosis Signaling [Jin Z et al. Cell 137:721 (2009)] ● Death receptor ligation induces polyubiquitination of caspase-8, through a previously unknown interaction of the DISC with a cullin3 (CUL3)-based E3 ligase. ● CUL3-mediated caspase-8 polyubiquitination required the RING box protein RBX1, whereas the deubiquitinase A20 reversed thismodification. ● The ubiquitin-binding protein p62/sequestosome-1 promoted aggregation of CUL3-modified caspase-8 within p62-dependent foci, leading to full activation and processing of the enzyme and driving commitment to cell death.
12.	Insulin signaling: Phosphorylation of IRS1 S307 by JNK	● The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 [Aguirre V et al. J Biol Chem 275:9047 (2000] ● Tumor necrosis factor a (TNFa) inhibits insulin action, in part, through serine phosphorylation of IRS proteins. ● TNFa promotes multipotential signal transduction cascades, including the activation of the Jun NH2-terminal kinase (JNK). ● Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFa on insulin-stimulated tyrosine phosphorylation of IRS-1. ● These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFa on IRS-1 function.
	Insulin signaling: JNK in obesity and insulin resistance	● A central role for JNK in obesity and insulin resistance [Hirosuml J et al. Nature 420:333 (2002)] ● Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus. ● The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. ● Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. ● Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.