Biomedical subjects

Cheh Peng Lim

Publications and source records attributed to Cheh Peng Lim.

3 recordsLinked to original sources

PubMed2006

Structure, function, and regulation of STAT proteins.

The Signal Transducer and Activator of Transcription (STAT) family of proteins was first discovered in the 1990's as key proteins in cytokine signaling. Since then, the field has greatly advanced in the past 15 years, providing significant insight into the structure, function, and regulation of STATs. STATs are latent cytoplasmic transcription factors consisting of seven mammalian members. They are Tyr phosphorylated upon activation, a post-translational modification critical for dimerization, nuclear import, DNA binding, and transcriptional activation. In recent years, unphosphorylated STATs have also been observed to dimerize and drive transcription, albeit by yet an obscure mechanism. In addition, the function of cytoplasmic STATs is beginning to emerge. Here, we describe the structure, function, and regulation of both unphosphorylated and phosphorylated STATs. STAT isoforms from alternative splicing or proteolytic processing, and post-translational modifications affecting STAT activities are also discussed.

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PubMed2006

Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin.

Stat3 is a member of the signal transducer and activator of transcription family, which is important in cytokine signaling. Gene ablation studies have revealed a requirement for Stat3 in diverse biological processes (Akira, S. 2000. Oncogene. 19: 2607-2611; Levy, D.E., and C.K. Lee. 2002. J. Clin. Invest. 109:1143-1148). Previously, the function of Stat3 had been attributed exclusively to its transcriptional activity in the nucleus. In this study, we reveal an interaction between Stat3 and the microtubule (MT)-destabilizing protein stathmin. Stathmin did not overtly affect ligand-stimulated Stat3 activation. In contrast, the expression of Stat3 is required for the stabilization of MTs and cell migration. We further demonstrate that Stat3-containing cells are resistant to the MT-destabilizing effect of stathmin overexpression. In addition, down-regulation of stathmin protein levels in Stat3-deficient cells partially reversed the MT and migration deficiencies. Recombinant Stat3 was also capable of reversing stathmin inhibition of tubulin polymerization in vitro. Our results indicate that Stat3 modulates the MT network by binding to the COOH-terminal tubulin-interacting domain of stathmin and antagonizing its MT destabilization activity.

Animals↗

PubMed2005

The LIM/homeodomain protein Islet1 recruits Janus tyrosine kinases and signal transducer and activator of transcription 3 and stimulates their activities.

Islet1 (Isl1) belongs to the LIM homeodomain transcription factor family. Its roles in differentiation of motor neurons and organogenesis of pancreas and heart have been revealed. However, less is known about its regulatory mechanism and the target genes. In this study, we identified interactions between Isl1 and Janus tyrosine kinase (JAK), as well as signal transducer and activator of transcription (Stat)3, but not Stat1 and Stat5, in mammalian cells. We found that Isl1 not only forms a complex with Jak1 and Stat3 but also triggers the tyrosine phosphorylation of Jak1 and its kinase activity, thereby elevating the tyrosine phosphorylation, DNA binding activity, and target gene expression of Stat3. In vivo, the tyrosine-phosphorylated Stat3 was colocalized with Isl1 in the nucleus of the mouse motor neurons in spinal cord after nerve injury. Correspondingly, electroporation of Isl1 and Stat3 into the neural tube of chick embryos resulted in the activation of a reporter gene expression controlled by a Stat3 regulatory sequence, and cotransfection of Isl1 and Stat3 promoted the proliferation of the mouse motor neuron cells. Our data suggest a novel role of Isl1 as an adaptor for Jak1 and Stat3 and reveal a possible functional link between LIM homeodomain transcription factors and the Jak-Stat pathway.

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