Mitogen-activated Protein Kinase Kinase Kinase 1 Activates Androgen Receptor-dependent Transcription and Apoptosis in Prostate Cancer

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1999 Jun 22

PMID 10373563

Citations 64

Authors

A Chari

A A Palladino

N A Craft

C L Sawyers

Affiliations

Soon will be listed here.

Abstract

Mitogen-activated protein (MAP) kinases phosphorylate the estrogen receptor and activate transcription from estrogen receptor-regulated genes. Here we examine potential interactions between the MAP kinase cascade and androgen receptor-mediated gene regulation. Specifically, we have studied the biological effects of mitogen-activated protein kinase kinase kinase 1 (MEKK1) expression in prostate cancer cells. Our findings demonstrate that expression of constitutively active MEKK1 induces apoptosis in androgen receptor-positive but not in androgen receptor-negative prostate cancer cells. Reconstitution of the androgen receptor signaling pathway in androgen receptor-negative prostate cancer cells restores MEKK1-induced apoptosis. MEKK1 also stimulates the transcriptional activity of the androgen receptor in the presence or absence of ligand, whereas a dominant negative mutant of MEKK1 impairs activation of the androgen receptor by androgen. These studies demonstrate an unanticipated link between MEKK1 and hormone receptor signaling and have implications for the molecular basis of hormone-independent prostate cancer growth.

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References

Marcelli M, Tilley W, Wilson C, GRIFFIN J, Wilson J, McPhaul M . Definition of the human androgen receptor gene structure permits the identification of mutations that cause androgen resistance: premature termination of the receptor protein at amino acid residue 588 causes complete androgen resistance. Mol Endocrinol. 1990; 4(8):1105-16. DOI: 10.1210/mend-4-8-1105. View

Fanger G, Widmann C, Porter A, Sather S, Johnson G, Vaillancourt R . 14-3-3 proteins interact with specific MEK kinases. J Biol Chem. 1998; 273(6):3476-83. DOI: 10.1074/jbc.273.6.3476. View

Veldscholte J, Berrevoets C, Ris-Stalpers C, Kuiper G, Jenster G, Trapman J . The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992; 41(3-8):665-9. DOI: 10.1016/0960-0760(92)90401-4. View

Shi Y, Glynn J, Guilbert L, Cotter T, Bissonnette R, Green D . Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science. 1992; 257(5067):212-4. DOI: 10.1126/science.1378649. View

Prins G, Sklarew R, PERTSCHUK L . Image analysis of androgen receptor immunostaining in prostate cancer accurately predicts response to hormonal therapy. J Urol. 1998; 159(3):641-9. View

Widmann C, Gibson S, Johnson G . Caspase-dependent cleavage of signaling proteins during apoptosis. A turn-off mechanism for anti-apoptotic signals. J Biol Chem. 1998; 273(12):7141-7. DOI: 10.1074/jbc.273.12.7141. View

Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H . Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci U S A. 1998; 95(7):3537-42. PMC: 19871. DOI: 10.1073/pnas.95.7.3537. View

Faris M, Kokot N, Latinis K, Kasibhatla S, Green D, Koretzky G . The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression. J Immunol. 1998; 160(1):134-44. View

Deak J, Cross J, Lewis M, Qian Y, Parrott L, Distelhorst C . Fas-induced proteolytic activation and intracellular redistribution of the stress-signaling kinase MEKK1. Proc Natl Acad Sci U S A. 1998; 95(10):5595-600. PMC: 20423. DOI: 10.1073/pnas.95.10.5595. View

10.

Wise S, Burmeister L, Zhou X, Bubulya A, Oberfield J, Birrer M . Identification of domains of c-Jun mediating androgen receptor transactivation. Oncogene. 1998; 16(15):2001-9. DOI: 10.1038/sj.onc.1201697. View

11.

Karin M . New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?. Cell. 1998; 93(4):487-90. DOI: 10.1016/s0092-8674(00)81177-0. View

12.

Yin M, Christerson L, Yamamoto Y, Kwak Y, Xu S, Mercurio F . HTLV-I Tax protein binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation. Cell. 1998; 93(5):875-84. DOI: 10.1016/s0092-8674(00)81447-6. View

13.

Zhou Q, Krebs J, Snipas S, Price A, Alnemri E, Tomaselli K . Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/p35 complex. Biochemistry. 1998; 37(30):10757-65. DOI: 10.1021/bi980893w. View

14.

Craft N, Shostak Y, Carey M, Sawyers C . A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999; 5(3):280-5. DOI: 10.1038/6495. View

15.

Lim D, Liu X, Sutkowski D, Braun E, Lee C, Kozlowski J . Growth of an androgen-sensitive human prostate cancer cell line, LNCaP, in nude mice. Prostate. 1993; 22(2):109-18. DOI: 10.1002/pros.2990220203. View

16.

Derijard B, Hibi M, Wu I, Barrett T, Su B, Deng T . JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994; 76(6):1025-37. DOI: 10.1016/0092-8674(94)90380-8. View

17.

Amati B, Land H . Myc-Max-Mad: a transcription factor network controlling cell cycle progression, differentiation and death. Curr Opin Genet Dev. 1994; 4(1):102-8. DOI: 10.1016/0959-437x(94)90098-1. View

18.

Brandstrom A, Westin P, Bergh A, Cajander S, Damber J . Castration induces apoptosis in the ventral prostate but not in an androgen-sensitive prostatic adenocarcinoma in the rat. Cancer Res. 1994; 54(13):3594-601. View

19.

Culig Z, Hobisch A, Cronauer M, Radmayr C, Trapman J, HITTMAIR A . Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res. 1994; 54(20):5474-8. View

20.

Ikonen T, Palvimo J, Kallio P, Reinikainen P, Janne O . Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation. Endocrinology. 1994; 135(4):1359-66. DOI: 10.1210/endo.135.4.7925097. View