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A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Mol Cell Biol 2013 Oct;33(20):4051-67

Date

08/21/2013

Pubmed ID

23959801

Pubmed Central ID

PMC3811686

DOI

10.1128/MCB.00021-13

Scopus ID

2-s2.0-84886885205   37 Citations

Abstract

Dysregulated Raf/MEK/extracellular signal-regulated kinase (ERK) signaling, a common hallmark of tumorigenesis, can trigger innate tumor-suppressive mechanisms, which must be inactivated for carcinogenesis to occur. This innate tumor-suppressive signaling may provide a potential therapeutic target. Here we report that mortalin (HSPA9/GRP75/PBP74) is a novel negative regulator of Raf/MEK/ERK and may provide a target for the reactivation of tumor-suppressive signaling of the pathway in cancer. We found that mortalin is present in the MEK1/MEK2 proteome and is upregulated in human melanoma biopsy specimens. In different MEK/ERK-activated cancer cell lines, mortalin depletion induced cell death and growth arrest, which was accompanied by increased p21(CIP1) transcription and MEK/ERK activity. Remarkably, MEK/ERK activity was necessary for mortalin depletion to induce p21(CIP1) expression in B-Raf(V600E)-transformed cancer cells regardless of their p53 status. In contrast, in cell types exhibiting normal MEK/ERK status, mortalin overexpression suppressed B-Raf(V600E)- or ΔRaf-1:ER-induced MEK/ERK activation, p21(CIP1) expression, and cell cycle arrest. Other HSP70 family chaperones could not effectively replace mortalin for p21(CIP1) regulation, suggesting a unique role for mortalin. These findings reveal a novel mechanism underlying p21(CIP1) regulation in MEK/ERK-activated cancer and identify mortalin as a molecular switch that mediates the tumor-suppressive versus oncogenic result of dysregulated Raf/MEK/ERK signaling. Our study also demonstrates that p21(CIP1) has dual effects under mortalin-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death.

Author List

Wu PK, Hong SK, Veeranki S, Karkhanis M, Starenki D, Plaza JA, Park JI

Authors

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
Pui Kei Wu PhD Instructor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Cycle Checkpoints
Cell Death
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21
Gene Expression Regulation, Neoplastic
Genes, Reporter
HSP70 Heat-Shock Proteins
Humans
Luciferases
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Proto-Oncogene Proteins B-raf
Signal Transduction
Tumor Suppressor Protein p53
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a