Mixed lineage kinase (MLK) family members are not involved in androgen regulation of prostatic proliferation or apoptosis

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Once paracrine growth factors are secreted by androgen receptor expressing prostatic stromal cells, they diffuse across the basement membrane of glandular acini, where they bind to epithelial cell surface receptors. This binding stimulates signaling pathways that regulate both the rate of proliferation and apoptosis of prostate epithelial cells. In the present studies, the role of mixed lineage kinases (MLKs) in these signaling processes were studied using a pharmacological approach. METHODS. The indolocarbazole CEP-1347 (KT 7515) is a potent inhibitor of kinase activity of MKLs. Male rats were treated with CEP-1347 (1 mg/kg of body weight/day) to determine whether inhibition of the MLKs can prevent androgen ablation (i.e. castration) induced apoptosis of prostatic epithelial cells, using as indexes total ventral prostatic DNA content and the percentage of ventral prostatic epithelial cells whose DNA can be terminal transferase end-labeled. In addition, animals previously castrated a week earlier were treated daily with either vehicle or CEP-1347 and exogenous androgen replacement to induce the proliferative regrowth of the prostatic epithelial cells. After 1 week of treatment, the total ventral prostatic DNA content in the vehicle vs. CEP-1347 groups was compared. RESULTS. Using the National Center for Bio-Informatics data bank, MLK2, MLK3, and DLK members of the MLK family are expressed by the normal prostate. Inhibition of the MLKs with CEP-1347 did not affect the kinetics of apoptosis of prostatic epithelial cells induced by androgen ablation. In addition, such MLK inhibition did not prevent androgen replacement induced proliferative regrowth of the prostate epithelium in castrated animals. CONCLUSION. Signaling through the MLK family is not involved in either the androgen-induced proliferation or the androgen ablation-induced apoptosis of prostatic epithelial cell in the rat.

Original languageEnglish (US)
Pages (from-to)67-70
Number of pages4
JournalProstate
Volume48
Issue number2
DOIs
StatePublished - Jul 1 2001

Fingerprint

Androgens
Phosphotransferases
Epithelial Cells
Apoptosis
Prostate
DNA
Castration
Androgen Receptors
Cell Surface Receptors
Stromal Cells
Transferases
Computational Biology
Basement Membrane
3,9-bis((ethylthio)methyl)-K-252a
Intercellular Signaling Peptides and Proteins
Epithelium
Body Weight
Databases
Pharmacology
Inhibition (Psychology)

Keywords

  • Androgen regulation
  • Epithelial cells
  • Mixed lineage kinase

ASJC Scopus subject areas

  • Urology

Cite this

Mixed lineage kinase (MLK) family members are not involved in androgen regulation of prostatic proliferation or apoptosis. / Gao, Jin; Isaacs, John Tod.

In: Prostate, Vol. 48, No. 2, 01.07.2001, p. 67-70.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND. Once paracrine growth factors are secreted by androgen receptor expressing prostatic stromal cells, they diffuse across the basement membrane of glandular acini, where they bind to epithelial cell surface receptors. This binding stimulates signaling pathways that regulate both the rate of proliferation and apoptosis of prostate epithelial cells. In the present studies, the role of mixed lineage kinases (MLKs) in these signaling processes were studied using a pharmacological approach. METHODS. The indolocarbazole CEP-1347 (KT 7515) is a potent inhibitor of kinase activity of MKLs. Male rats were treated with CEP-1347 (1 mg/kg of body weight/day) to determine whether inhibition of the MLKs can prevent androgen ablation (i.e. castration) induced apoptosis of prostatic epithelial cells, using as indexes total ventral prostatic DNA content and the percentage of ventral prostatic epithelial cells whose DNA can be terminal transferase end-labeled. In addition, animals previously castrated a week earlier were treated daily with either vehicle or CEP-1347 and exogenous androgen replacement to induce the proliferative regrowth of the prostatic epithelial cells. After 1 week of treatment, the total ventral prostatic DNA content in the vehicle vs. CEP-1347 groups was compared. RESULTS. Using the National Center for Bio-Informatics data bank, MLK2, MLK3, and DLK members of the MLK family are expressed by the normal prostate. Inhibition of the MLKs with CEP-1347 did not affect the kinetics of apoptosis of prostatic epithelial cells induced by androgen ablation. In addition, such MLK inhibition did not prevent androgen replacement induced proliferative regrowth of the prostate epithelium in castrated animals. CONCLUSION. Signaling through the MLK family is not involved in either the androgen-induced proliferation or the androgen ablation-induced apoptosis of prostatic epithelial cell in the rat.",
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N2 - BACKGROUND. Once paracrine growth factors are secreted by androgen receptor expressing prostatic stromal cells, they diffuse across the basement membrane of glandular acini, where they bind to epithelial cell surface receptors. This binding stimulates signaling pathways that regulate both the rate of proliferation and apoptosis of prostate epithelial cells. In the present studies, the role of mixed lineage kinases (MLKs) in these signaling processes were studied using a pharmacological approach. METHODS. The indolocarbazole CEP-1347 (KT 7515) is a potent inhibitor of kinase activity of MKLs. Male rats were treated with CEP-1347 (1 mg/kg of body weight/day) to determine whether inhibition of the MLKs can prevent androgen ablation (i.e. castration) induced apoptosis of prostatic epithelial cells, using as indexes total ventral prostatic DNA content and the percentage of ventral prostatic epithelial cells whose DNA can be terminal transferase end-labeled. In addition, animals previously castrated a week earlier were treated daily with either vehicle or CEP-1347 and exogenous androgen replacement to induce the proliferative regrowth of the prostatic epithelial cells. After 1 week of treatment, the total ventral prostatic DNA content in the vehicle vs. CEP-1347 groups was compared. RESULTS. Using the National Center for Bio-Informatics data bank, MLK2, MLK3, and DLK members of the MLK family are expressed by the normal prostate. Inhibition of the MLKs with CEP-1347 did not affect the kinetics of apoptosis of prostatic epithelial cells induced by androgen ablation. In addition, such MLK inhibition did not prevent androgen replacement induced proliferative regrowth of the prostate epithelium in castrated animals. CONCLUSION. Signaling through the MLK family is not involved in either the androgen-induced proliferation or the androgen ablation-induced apoptosis of prostatic epithelial cell in the rat.

AB - BACKGROUND. Once paracrine growth factors are secreted by androgen receptor expressing prostatic stromal cells, they diffuse across the basement membrane of glandular acini, where they bind to epithelial cell surface receptors. This binding stimulates signaling pathways that regulate both the rate of proliferation and apoptosis of prostate epithelial cells. In the present studies, the role of mixed lineage kinases (MLKs) in these signaling processes were studied using a pharmacological approach. METHODS. The indolocarbazole CEP-1347 (KT 7515) is a potent inhibitor of kinase activity of MKLs. Male rats were treated with CEP-1347 (1 mg/kg of body weight/day) to determine whether inhibition of the MLKs can prevent androgen ablation (i.e. castration) induced apoptosis of prostatic epithelial cells, using as indexes total ventral prostatic DNA content and the percentage of ventral prostatic epithelial cells whose DNA can be terminal transferase end-labeled. In addition, animals previously castrated a week earlier were treated daily with either vehicle or CEP-1347 and exogenous androgen replacement to induce the proliferative regrowth of the prostatic epithelial cells. After 1 week of treatment, the total ventral prostatic DNA content in the vehicle vs. CEP-1347 groups was compared. RESULTS. Using the National Center for Bio-Informatics data bank, MLK2, MLK3, and DLK members of the MLK family are expressed by the normal prostate. Inhibition of the MLKs with CEP-1347 did not affect the kinetics of apoptosis of prostatic epithelial cells induced by androgen ablation. In addition, such MLK inhibition did not prevent androgen replacement induced proliferative regrowth of the prostate epithelium in castrated animals. CONCLUSION. Signaling through the MLK family is not involved in either the androgen-induced proliferation or the androgen ablation-induced apoptosis of prostatic epithelial cell in the rat.

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