Regulation of MAP kinases by the VHR dual-specific phosphatase: implications for cell growth and differentiation.
Although it is well established that a transient activation of the mitogen-activated protein kinases Erk and Jnk is a crucial step in most growth promoting signaling pathways, it has also been demonstrated that a prolonged activation of these kinases can induce differentiation, cell cycle arrest, and cell senescence. We recently found that the expression of the 21-kDa human Vaccinia H1-related (VHR) dual-specific phosphatase fluctuates during cell cycle progression and affects Erk and Jnk activity in a cell cycle-dependent manner. Cells lacking VHR arrested at the G(1)/S and G(2)/M transitions of the cell cycle and exhibited senescence phenotypes. Cells lacking VHR upregulated p21(Cip/Waf1) and downregulated many genes for cell cycle regulators, DNA replication, transcription, and mRNA processing. In the absence of VHR, the serum-induced activation of Jnk and Erk was further elevated and was required for the G(1)/S and G(2)/M blocks, which were attenuated upon Jnk and Erk inhibition. Collectively, VHR provides a long sought layer in the regulation of Jnk and Erk during cell cycle progression thereby contributing to cell cycle arrest, differentiation or senescence.
Cerignoli
Fabio
F
The Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Rahmouni
Souad
S
Ronai
Ze'ev
Z
Mustelin
Tomas
T
D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D054640:Dual Specificity Phosphatase 3; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*
D018797:Cell Cycle Proteins; D020928:Mitogen-Activated Protein Kinases; C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3; D017027:Protein Tyrosine Phosphatases