Repression of the insulin receptor promoter by the tumor suppressor gene product p53: a possible mechanism for receptor overexpression in breast cancer.

"insulin" "binds to" "insulin receptor"
"insulin receptor" "is a" "protein"
"a promoter" "increases" "transcription process"
"insulin receptor promoter" "promotes" "insulin receptor"
"p53 protein" "suppresses" "tumors"
"insulin receptor promoter" "is decreased by" "p53 protein"
"insulin receptor" "is overexpressed by" "breast cancer tumor cells"

"this" "authored by" "Webster NJ"
"this" "authored by "Resnik JL"
"this" "authored by" "Reichart DB"
"this" "authored by" "Strauss B"
"this" "authored by" "Haas M"
"this" "authored by" "Seely BL"

"this" "authored at" "Department of Medicine"
"this" "authored at" "Division of Endocrinology and Metabolism"
"this" "authored at" "University of California"
"this" "authored at" "San Diego"
"this" "authored at" "La Jolla"
"this" "authored at" "California 92093"
"this" "authored at" "USA"

There is strong evidence to suggest that insulin and insulin-like growth factor (IGF)-I may be important for tumor growth.

"insulin" "is required for growth of" "breast cancer tumor cells"
"insulin-like growth factor" is required for growth of breast cancer tumor cells

Both the insulin and IGF-I receptors (IGF-IR) are overexpressed in breast cancer, and antibody blockade of the IGF-IR inhibits the growth of some breast cancer cell lines.

"breast cancer tumor cells" "overexpress" "insulin"
"breast cancer tumor cells" "overexpress" "insulin-like growth factor"

"insulin-like growth factor receptor" "antibody blockade decreases" "breast cancer tumor cells"

Furthermore, expression of an insulin receptor (IR) in a normal mammary epithelial cell line causes insulin-dependent transformation.

"insulin receptor" "transforms into tumor cells" "normal mammary epithelial cells"

Functional inactivation of p53 is also very frequent in many tumors.

"mutated p53 protein" "is associated with" "breast cancer tumor cells"

In this paper, we investigated whether inactivation of p53 might be involved in the overexpression of the IR in malignancy, specifically breast cancer.

"p53 protein" "overexpression is associated with increased" "[insulin receptor]"

We demonstrate a positive correlation between IR and IGF-IR levels and p53 overexpression in primary human breast malignancies.

"p53 protein" "overexpression is associated with increased" "[insulin-like growth factor receptor]"

To examine possible mechanisms by which p53 may regulate IR gene expression, we show that p53 can repress the IR promoter and that a dominant-negative p53 (248Q) can de-repress the promoter in cells containing normal p53.

"p53 protein" "regulates expression of " "insulin receptor"

"p53 protein" "represses" "insulin receptor promoter"

"mutated p53 protein" "does not repress" "insulin receptor promoter"

"dominant-negative p53 protein(248Q)" "is a kind of" "mutated p53 protein"

The p53 effect was shown to be mediated by C/EBP and Sp1 transcription factors.

"C/EBP" "is a" "transcription factor"

"Sp1" "is a" "transcription factor"

"C/EBP" "affects" "p53 protein"

"Sp1" "affects" "p53 protein"

We also documented that p53-null mice had elevated levels of Sp1, but not C/EBPalpha, and that insulin binding to liver extracts was increased compared to wild-type controls.

"p53 protein lacking mice" "have elevated levels of" "Sp1"

"p53 protein lacking mice" "have normal levels of" "C/EBP"

These results suggest that p53 inactivation may lead to an up-regulation of genes, such as the IR, that are dependent on these transcription factors.

"p53 protein" "inactivation up-regulates expression of" "insulin receptor protein"

Standard Nomenclature MeSH Terms
{
Animal
Base Sequence
Binding, Competitive
Breast Neoplasms/metabolism*
DNA-Binding Proteins/metabolism*
Female
Genes, Reporter
Human
Insulin/metabolism*
Insulin-Like Growth Factor I/metabolism*
Mice
Molecular Sequence Data
Nuclear Proteins/metabolism*
Promoter Regions (Genetics)*
Protein p53/physiology
Protein p53/metabolism*
Protein p53/deficiency
Receptor, Insulin/metabolism*
Receptor, Insulin/genetics
Receptor, IGF Type 1/metabolism*
Support, Non-U.S. Gov't
Support, U.S. Gov't, Non-P.H.S.
Support, U.S. Gov't, P.H.S.
Transcription Factor, Sp1/metabolism*
Transfection
}

Standard Nomenclature Substances
{

Substances:
Insulin-Like Growth Factor I
Insulin
Transcription Factor, Sp1
Protein p53
Nuclear Proteins
DNA-Binding Proteins
C-EBP nuclear protein
Receptor, IGF Type 1
Receptor, Insulin
}

Funded By
{
Grant support:
DK 44643/DK/NIDDK
DK 02162/DK/NIDDK
}