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Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors

Oncogene volume 23, pages 5978–5985 (2004)Cite this article

Abstract

MKK4, located in close proximity to p53 gene, is thought to be a tumor suppressor and a metastasis suppressor gene. A low-rate MKK4 gene alteration has been found in a few tumor types, including breast and pancreatic. A suppressor activity for prostate and ovarian tumor metastasis has also been suggested. To understand the pathobiologic roles of MKK4 in tumorigenesis, we examined the phenotypic changes in response to perturbation of the MKK4 expression in breast and pancreatic cancer cell lines. Ectopic expression of MKK4 by adenoviral delivery in MKK4-negative cancer lines stimulated the cell proliferation and invasion, whereas knockdown of MKK4 expression by small interference RNA in an MKK4-positive breast cancer cell line, MDA-MB-231, resulted in decreased anchorage-independent growth, suppressed tumor growth in mouse xenograft model, and increased cell susceptibility to apoptosis brought by stress signals such as serum deprivation. These results argue that MKK4 functions as a pro-oncogenic molecule instead of a suppressor in breast and pancreatic tumors.

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Abbreviations

JNK:

c-JUN NH2-terminal kinase

LOH:

loss of heterozygosity

MAPK:

mitogen-activated protein kinase

MKK4:

mitogen-activated protein kinase kinase 4

MKK7:

mitogen-activated protein kinase kinase 7

MOI:

multiplicity of infection

PBS:

phosphate-buffered saline

PARP:

poly(ADP-ribose) polymerase

PCR:

polymerase chain reaction

PI:

propidium iodine

RT–PCR:

reverse transcriptase–PCR

siRNA:

small interference RNA

TUNEL:

terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling

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Acknowledgements

We thank Drs Roger Davis and Yang Shi for sharing plasmid constructs, Drs Timothy McDonnell and Eswaran Devarajan for valuable discussions, and Ms Lore Feldman for editorial comments.

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  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Lei Wang, Yong Pan & Jia Le Dai

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  1. Lei Wang
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Correspondence to Jia Le Dai.

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Wang, L., Pan, Y. & Dai, J. Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors. Oncogene 23, 5978–5985 (2004). https://doi.org/10.1038/sj.onc.1207802

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