Methylation of the calcitonin gene in human tumors

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Project Title: Methylation of the calcitonin gene in human tumors
Principal Investigators (PI): BAYLIN STEPHEN B
Project Number: 2R01CA043318-19
Organization: JOHNS HOPKINS UNIVERSITY
 
Project Description:
The overall goals of this grant are to: a) understand the role of epigenetic gene silencing in cancer through studying the function of novel genes which have aberrant promoter hypermethylation; and b) dissect molecular mechanisms by which this promoter change participates in transcriptional silencing and through which it arises during cancer evolution. In the first specific aim, we have created a mouse knockout model for HIC-1 (Hypermethylated-in-Cancer-1), a gene cloned by screening for hypermethylated loci in a frequent LOH area for human cancers, 17p13.3. Hic-1 mice manifest an age dependent, gender specific, tumor spectrum and the wild type allele is lost in the tumors solely through promoter methylation. The loss of Hic-1 also profoundly alters tumor spectrum and aggressiveness in p53 mice including appearance of breast cancers. We will create new models for breast and other cancers based on this loss of Hic-1 function as a requisite early step. In the second specific aim, we have identified the developmental gene, ephrin A1, as a direct transcriptional repression target of HIC-1. We will study the significance of this for HIC-1 anti-tumor effects by: a) exploring whether ephrin AlsiRNA knockdown in human breast cancer cells reproduces effects of exogenous over-expression of HIC-1; and b) targeting overexpression of ephrin A1 to breast epithelium in a transgenic mouse. In the third specific aim, we identify that different histone modifications (the "histone code") mark promoter regions of transcriptionally silent and hypermethylated genes versus these same genes when they are unmethylated and expressed. Drug induced (5-deoxy-azacytidine-DAC) reversal of the hypermethylation leads to gene re-expression and loss of the transcriptional silencing histone marks and gain of transcriptional activation marks. We are exploring the hypothesis that the demethylation triggers these events through directly activating transcription which then prompts a nucleosome switch involving variant histones to account for loss of the silencing histone marks and gain of the transcriptional activation histone modifications. In specific aim # 4, we explore whether methylation of lysine 9 of histone H3 serves as a signal for triggering DNA methylation associated with cancer gene silencing. Our data in studies of a hypermethylated p16 gene in colon cancer ceils indicates that this may be the case. We will determine, through ChIP localization assays, and gene knockdown and over-expression studies, which specific methyl K9:H3 methyltransferases may trigger this histone modification and thus may establish aberrant promoter DNA hypermethylation in cancer cells. A final specific aim links all of those above by exploring the hypothesis that specific chromatin changes may explain the gender differences in the spectrum of tumors seen in mice with disruption of the gene being studied in Specific Aims #'s 1 and 2.
 
Project Terms:
DNA methylation carcinogenesis gene induction /repression neoplasm /cancer genetics genetic transcription ephrins functional /structural genomics azacitidine tumor suppressor genes chromatin transcription factor neoplastic cell breast neoplasms gender difference mammary epithelium methyltransferase chromatin immunoprecipitation genetically modified animals laboratory mouse
Project Title: Methylation of the calcitonin gene in human tumors
Principal Investigators (PI): BAYLIN STEPHEN B
Project Number: 2R01CA043318-19
Organization: JOHNS HOPKINS UNIVERSITY
 
Project Categories:
• Natural Sciences > Experimental techniques > Genetic Engineering > Tracking experiments
 
Other Information:
Fiscal Year: 1986
Project Start Date: 30 September 1986
Project End Date: 31 May 2009
Administering Institute Or Center: CA
 
Project Funding Information:
Total Funding: $449,625
Year Funding Organization Total Funding, $
2004 NATIONAL CANCER INSTITUTE $449,625
Project Title: Methylation of the calcitonin gene in human tumors
Principal Investigators (PI): BAYLIN STEPHEN B
Project Number: 2R01CA043318-19
Organization: JOHNS HOPKINS UNIVERSITY
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Methylation of the calcitonin gene in human tumors
Principal Investigators (PI): BAYLIN STEPHEN B
Project Number: 2R01CA043318-19
Organization: JOHNS HOPKINS UNIVERSITY
 
Project number Project title Organization FY Funding Organization FY Total Cost
2R01CA043318-19Methylation of the Calcitonin Gene in Human TumorsJOHNS HOPKINS UNIVERSITY2004NATIONAL CANCER INSTITUTE
$449,625
5P50CA058184-10SPORE in Lung CancerJOHNS HOPKINS UNIVERSITY2004NATIONAL CANCER INSTITUTE
$2,491,531
5R01CA043318-18METHYLATION OF THE CALCITONIN GENE IN HUMAN TUMORSJOHNS HOPKINS UNIVERSITY2003NATIONAL CANCER INSTITUTE
$435,948
2P50CA058184-09SPORE in Lung CancerJOHNS HOPKINS UNIVERSITY2003NATIONAL CANCER INSTITUTE
$2,500,000
5R01CA043318-17METHYLATION OF THE CALCITONIN GENE IN HUMAN TUMORSJOHNS HOPKINS UNIVERSITY2002NATIONAL CANCER INSTITUTE
$424,197
3P50CA058184-08S2SPORE IN LUNG CANCERJOHNS HOPKINS UNIVERSITY2002NATIONAL CANCER INSTITUTE
$1,826,707
5R01CA043318-16METHYLATION OF THE CALCITONIN GENE IN HUMAN TUMORSJOHNS HOPKINS UNIVERSITY2001NATIONAL CANCER INSTITUTE
$412,892
3P50CA058184-08S1SPORE IN LUNG CANCERJOHNS HOPKINS UNIVERSITY2001NATIONAL CANCER INSTITUTE
$1,829,926
5R01CA054396-10DNA METHYLTRANSFERASE GENE EXPRESSION IN COLON CANCERJOHNS HOPKINS UNIVERSITY2000NATIONAL CANCER INSTITUTE
$362,833
5R01CA043318-15METHYLATION OF THE CALCITONIN GENE IN HUMAN TUMORSJOHNS HOPKINS UNIVERSITY2000NATIONAL CANCER INSTITUTE
$402,935
5P50CA058184-08-0011LUNG CANCER--CAREER DEVELOPMENTJOHNS HOPKINS UNIVERSITY2000NATIONAL CANCER INSTITUTE
$131,614
5P50CA058184-08-0002DNA METHYLATION/NEUROENDOCRINE DIFFERENTIATION--MARKING EARLY STATE LUNG CANCERJOHNS HOPKINS UNIVERSITY2000NATIONAL CANCER INSTITUTE
$131,614
5P50CA058184-08-0010LUNG CANCER--DEVELOPMENTAL RESEARCH PROGRAMJOHNS HOPKINS UNIVERSITY2000NATIONAL CANCER INSTITUTE
$131,614
5P50CA058184-08SPORE IN LUNG CANCERJOHNS HOPKINS UNIVERSITY2000NATIONAL CANCER INSTITUTE
$1,776,628
5P50CA058184-11SPORE in Lung CancerJOHNS HOPKINS UNIVERSITY2005NATIONAL CANCER INSTITUTE
$2,490,165
5R01CA043318-20Methylation of the Calcitonin Gene in Human TumorsJOHNS HOPKINS UNIVERSITY2005NATIONAL CANCER INSTITUTE
$449,625
1R01CA116160-01Developmental pathways, cancer, and DNA hypermethylationJOHNS HOPKINS UNIVERSITY2005NATIONAL CANCER INSTITUTE
$321,678
2P30CA006973-44-0002PROGRAM LEADERSHIPJOHNS HOPKINS UNIVERSITY2006NATIONAL CANCER INSTITUTE
$285,854
2P30CA006973-44-9035MICROARRAYJOHNS HOPKINS UNIVERSITY2006NATIONAL CANCER INSTITUTE
$95,328
2P30CA006973-44-9047CRCJOHNS HOPKINS UNIVERSITY2006NATIONAL CANCER INSTITUTE
$48,571
Project Title: Methylation of the calcitonin gene in human tumors
Principal Investigators (PI): BAYLIN STEPHEN B
Project Number: 2R01CA043318-19
Organization: JOHNS HOPKINS UNIVERSITY
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Methylation of the calcitonin gene in human tumors
Principal Investigators (PI): BAYLIN STEPHEN B
Project Number: 2R01CA043318-19
Organization: JOHNS HOPKINS UNIVERSITY
 
Title Abstract Authors Year Rel
Hypermethylation of a small CpGuanine-rich region correlates with loss of activator protein-2alpha expression during progression of breast cancer. Cancer research.. 2004 Mar 1 64 (5) :1611-20 Douglas, Donna B; Akiyama, Yoshimitsu; Carraway, Hetty; Belinsky, Steven A; Esteller, Manel; Gabrielson, Edward; Weitzman, Sigmund; Williams, Trevor; Herman, James G; Baylin, Stephen B 2004