SOCS: Its Regulation And Role In Oncogenesis
Chao-lan Yu
Vanderbilt University Medical Center Nashville, Tn 372036869
Grant 1R01CA107210-01A2 from National Cancer Institute IRG: TCB
Abstract: The suppressor of cytokine signaling (SOCS)- genes, SOCS1 and SOCS3, are critical targets of signal transducer and activator of transcription (STAT) pathways, providing normal negative feed-back control of signaling by cytokines and growth factors. Consistent with STAT activation in many tumor cells, SOCS1 expression is silenced in human cancer and enforced SOCS1 expression inhibits tumorigenesis. SOCS3 is closely related to SOCS1, but its regulation and role in oncogenesis remain largely unknown. Our preliminary studies find that cells transformed by Lck exhibit active STATS but fail to express both SOCS genes. In contrast to SOCS1 silencing by DNA methylation, defect of SOCS3 expression may be linked to the absence of STAT5b phosphorylation on non-conserved serine sites identified by our mass spectrometry. Additional preliminary studies show that SOCS3 associates with Lck in cells and becomes tyrosine-phosphorylated, and ectopic SOCS3 expression results in short-term growth suppression of Lck-transformed cells. Our long-term objectives are to determine how expression of different SOCS genes is disrupted in malignancies and to gain new mechanistic insights of their roles as tumor suppressors in various tumor models. This proposal focuses on the regulation of SOCS3 gene expression and protein functions. Aim 1 will determine the role of novel STAT5b serine phosphorylation in SOCS3 expression. We propose to define the functional STAT5b serine phosphorylation sites and elucidate its role in STAT5b-dependent assembly of transcriptional complex on the SOCS3 promoter in the context of chromatin. Aim 2 will test our hypothesis that SOCS3 and Lck proteins mutually regulate each other s functions and characterize the underlying mechanism. We further propose that a tyrosine mutant of SOCS3 is more potent than wild-type SOCS3 in suppressing Lck-mediated oncogenesis. In Aim 3, different SOCS3 proteins will be expressed in Lck-transformed LSTRA cells to evaluate their tumor-suppressing activities both in culture and in mice. The possibility to restore endogenous SOCS3 expression will also be tested with potential gain-of-function STAT5b mutants in LSTRA. Using Lck as a model system, we will start to define molecular details underlying the differences between SOCS1 and SOCS3 in their gene regulation and protein functions. Functional characterization of novel serine phosphorylation sites in STAT5b will further establish a new paradigm for its role in regulating STAT signaling and STAT-mediated gene expression. Relevance SOCS proteins are normally produced by cells to turn off signals that stimulate their growth. Many cancer cells lose expression of these potential tumor suppressors. Studies proposed here will help us better understand why SOCS genes are not expressed in human cancer and how SOCS proteins may function differently in tumor cells. Collectively they will reveal potentially new targets for cancer therapy.
Keywords: neoplasm /cancer, phosphorylation, role, gene, mutant, protein, serine, tyrosine
Project start date: 2006-09-01
Project end date: 2007-03-31
1R01CA107210-01A2 (2006): $244550
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Chao-lan Yu
SOCS: ITS REGULATION AND ROLE IN ONCOGENESIS
Chao-lan Yu
Rosalind Franklin Univ Of Medicine & Sci, 3333 Green Bay Rd, North Chicago, Il 60064
Grant 5R01CA107210-06 from National Cancer Institute
Abstract: The suppressor of cytokine signaling (SOCS)- genes, SOCS1 and SOCS3, are critical targets of signal transducer and activator of transcription (STAT) pathways, providing normal negative feed-back control of signaling by cytokines and growth factors. Consistent with STAT activation in many tumor cells, SOCS1 expression is silenced in human cancer and enforced SOCS1 expression inhibits tumorigenesis. SOCS3 is closely related to SOCS1, but its regulation and role in oncogenesis remain largely unknown. Our preliminary studies find that cells transformed by Lck exhibit active STATS but fail to express both SOCS genes. In contrast to SOCS1 silencing by DNA methylation, defect of SOCS3 expression may be linked to the absence of STAT5b phosphorylation on non-conserved serine sites identified by our mass spectrometry. Additional preliminary studies show that SOCS3 associates with Lck in cells and becomes tyrosine-phosphorylated, and ectopic SOCS3 expression results in short-term growth suppression of Lck-transformed cells. Our long-term objectives are to determine how expression of different SOCS genes is disrupted in malignancies and to gain new mechanistic insights of their roles as tumor suppressors in various tumor models. This proposal focuses on the regulation of SOCS3 gene expression and protein functions. Aim 1 will determine the role of novel STAT5b serine phosphorylation in SOCS3 expression. We propose to define the functional STAT5b serine phosphorylation sites and elucidate its role in STAT5b-dependent assembly of transcriptional complex on the SOCS3 promoter in the context of chromatin. Aim 2 will test our hypothesis that SOCS3 and Lck proteins mutually regulate each other´s functions and characterize the underlying mechanism. We further propose that a tyrosine mutant of SOCS3 is more potent than wild-type SOCS3 in suppressing Lck-mediated oncogenesis. In Aim 3, different SOCS3 proteins will be expressed in Lck-transformed LSTRA cells to evaluate their tumor-suppressing activities both in culture and in mice. The possibility to restore endogenous SOCS3 expression will also be tested with potential gain-of-function STAT5b mutants in LSTRA. Using Lck as a model system, we will start to define molecular details underlying the differences between SOCS1 and SOCS3 in their gene regulation and protein functions. Functional characterization of novel serine phosphorylation sites in STAT5b will further establish a new paradigm for its role in regulating STAT signaling and STAT-mediated gene expression. Relevance SOCS proteins are normally produced by cells to turn off signals that stimulate their growth. Many cancer cells lose expression of these potential tumor suppressors. Studies proposed here will help us better understand why SOCS genes are not expressed in human cancer and how SOCS proteins may function differently in tumor cells. Collectively they will reveal potentially new targets for cancer therapy
Keywords: ABL; ATP[{..}]protein-tyrosine O-phosphotransferase; Abelson Murine Leukemia Viral Oncogene Homolog; Address; Affect; Affinity; Back; Biological Models; CIS Gene; CIS protein; CIS-1 Gene; CIS-1 Protein; CISH; CISH Protein; CISH gene; Cancer Treatment; Cancers; Cell Communication and Signaling; Cell Signaling; Cells; Cellular Expansion; Cellular Growth; Chromatin; Complex; Cytokine Inducible SH2-Containing Protein; Cytokine Signal Transduction; Cytokine Signaling; Cytokine-Inducible Inhibitor of Signaling Type 1B; Cytokine-Inducible Inhibitor of Signaling Type 1B Gene; Cytokine-Inducible SH2-Containing Protein Gene; DNA Binding; DNA Binding Interaction; DNA Methylation; Defect; Dorsum; EC 2.7; EPH- and ELK-Related Tyrosine Kinase; EPH-and ELK-Related Kinase; EPHA8; Ectopic Expression; EphA8 Protein; Ephrin Type-A Receptor 8; Ephrin Type-A Receptor 8 Precursor; Exhibits; Family; Family member; Feedback; Frequencies (time pattern); Frequency; G18; G18 Gene; GFAC; Gene Action Regulation; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Regulation; Gene Regulation Process; Gene Targeting; Generalized Growth; Genes; Growth; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HEK3; Human; Human, General; Hyperactive behavior; Hyperactivity; Hyperactivity, Motor; Hyperkinesia; Hyperkinesis; Hyperkinetic Movements; Intracellular Communication and Signaling; Kinases; L-Serine; L-Tyrosine; Leukemogenesis/Lymphomagenesis; Link; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Lymphocyte-Specific Protein-Tyrosine Kinase; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Man (Taxonomy); Man, Modern; Mass Spectrum; Mass Spectrum Analysis; Mediating; Mice; Mining; Minings; Model System; Modeling; Models, Biologic; Molecular; Molecular Target; Murine; Mus; Nuclear; Oncogene ABL1; Oncogenesis; Oncogenic; PTK; Pathway interactions; Phosphorylation; Phosphotransferases; Photometry/Spectrum Analysis, Mass; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Protein Phosphorylation; Protein Tyrosine Kinase; Protein Tyrosine Kinase EEK; Protein Tyrosine Kinase p56(lck); Proteins; Proto-Oncogene Protein c-lck; Proto-Oncogene Protein lck; Proto-Oncogene Tyrosine-Protein Kinase LCK; Regulation; Role; SOCS; SOCS Gene; STAT protein; STAT3; STAT3 gene; Serine; Serine Phosphorylation Site; Signal Pathway; Signal Transducer and Activator of Transcription; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Protein; Site; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Suppressor of Cytokine Signaling; Suppressor of Cytokine Signaling Gene; T-Cell Specific Protein Tyrosine Kinase; TYR; Targetings, Gene; Testing; Tissue Growth; Transcription Activation; Transcriptional Activation; Transphosphorylases; Tumor Cell; Tumor Suppressor Proteins; Tyrosine; Tyrosine Kinase; Tyrosine, L-isomer; Tyrosine-Protein Kinase Receptor EEK; Tyrosine-Specific Protein Kinase; Tyrosylprotein Kinase; Up-Regulation; abl Oncogene; anticancer therapy; biological signal transduction; cancer cell; cancer therapy; cell growth; cell transformation; cis acting element; cytokine; experiment; experimental research; experimental study; feeding; gain of function; gene product; hydroxyaryl protein kinase; inhibitor; inhibitor/antagonist; insight; lck Kinase; leukemogenesis; malignancy; mutant; neoplasm/cancer; neoplastic cell; new approaches; novel; novel approaches; novel strategies; novel strategy; ontogeny; p56 lck; para-Tyrosine; pathway; protein function; research study; social role; src Oncogenes; transformed cells; tumor; tumor suppressor; tumorigenesis; tyrosyl protein kinase; v abl; v src; v-abl Genes; v-abl Oncogenes; v-src Genes; v-src Oncogenes
Project start date: 2006-09-01
Project end date: 2011-07-31
Budget start date: 27-AUG-2010
Budget end date: 31-JUL-2011
5R01CA107210-06 (2010): $235778
5R01CA107210-05 (2009): $235778
5R01CA107210-04 (2008): $234758
5R01CA107210-03 (2007): $235778
ROLES OF STAT-3 AND STAT-5 IN LCK MEDIATED ONCOGENESIS
Chao-lan Yu
Dana-farber Cancer Institute
44 Binney St
boston, Ma 02115
Grant 5F32CA079154-03 from National Cancer Institute IRG: ZRG2
Keywords: carcinogenesis, cell transformation, genetic transcription, protein kinase, protein structure /function, transcription factor biological signal transduction, genetic regulation immunoprecipitation
5F32CA079154-03 (2000): $42628
5F32CA079154-02 (1999): $40036
1F32CA079154-01 (1998): $31492