This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. Articles by Kulesz-Martin, M. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Articles by Kulesz-Martin, M.

Microtubule Disruption and Tumor Suppression by Mitogen-Activated Protein Kinase Phosphatase 4

Department of Dermatology, Oregon Health and Science University, Portland, Oregon

Requests for reprints: Yuangang Liu, Department of Dermatology, L468R, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. Phone: 503-418-4268; Fax: 503-418-4266; E-mail: liuy{at}ohsu.edu and Molly Kulesz-Martin, Department of Dermatology, L468R, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-9933; Fax: 503-418-4266; E-mail: kuleszma{at}ohsu.edu.

The extracellular signal-regulated kinase (Erk) is one of the downstream effectors of the Ras pathway whose activation is essential for the proliferation and survival of cancer cells. Erk activation is negatively regulated by mitogen-activated protein kinase (MAPK) phosphatases (MKP), which are generally up-regulated by Erk activation, thus forming a feedback loop for regulation of Erk activity. In searching for early alterations in the Ras pathway in epidermal carcinogenesis, we identified MKP4, a cytosolic MKP with specificity to not only Erk, but also, to a lesser extent, c-jun-NH₂-kinase and p38. MKP4 is down-regulated at initiation and lost at malignant conversion in a clonal model of epidermal carcinogenesis that lacks Ras mutation. The loss of MKP4 was associated with squamous cell carcinoma (SCC) but not benign papilloma clonal lineages and with independently induced SCC relative to benign tumors in mouse skin. Reconstitution of MKP4 expression in malignant tumor cells leads to cell death and tumor suppression. Unlike Erk inhibition that blocks cell cycle entry, MKP4 reconstitution resulted in G₂-M associated cell death and microtubule disruption. Thus, microtubule disruption by MKP4 provides a novel mechanism for tumor suppression by a cytosolic MKP and implies a novel therapeutic strategy through combined MAPK inhibitions that mimic the function of MKP4. [Cancer Res 2007;67(22):10711–9]

This article has been cited by other articles:

				T. Boutros, E. Chevet, and P. Metrakos Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer Pharmacol. Rev., September 1, 2008; 60(3): 261 - 310. [Abstract] [Full Text] [PDF]