Activation of TPA-response element present in human Lemur Tyrosine Kinase 2 ( lmtk2 ) gene increases its expression

Abstract

Regulatory elements present in the promoter of a gene drive the expression of the gene in response to various stimuli. Lemur Tyrosine Kinase 2 (LMTK2) is a membrane-anchored Serine/Threonine kinase involved in endosomal protein trafficking and androgen signaling amongst other processes. Previous studies have shown this protein to be of therapeutic importance in cystic fibrosis and prostate cancer. However, nothing is known about the endogenous expression of this protein and its regulation. In this study, we analyzed the gene encoding human LMTK2, to look for possible regulatory elements that could affect its expression. Interestingly, the human lmtk2 gene contains a consensus TPA (12- O-Tetradecanoylphorbol-13-acetate)-responsive element (TRE) in the region preceding its start codon. The element with the sequence TGAGTCA modulates LMTK2 expression in response to treatment with TPA, a synthetic Protein Kinase C (PKC) activator. It serves as the binding site for c-Fos, a member of the Activator Protein −1 (AP-1) transcription factor complex, which is transactivated by PKC. We observed that TPA, at low concentrations, increases the promoter activity of LMTK2, which leads to a subsequent increase in the mRNA transcript and protein levels. This modulation occurs through binding of the AP-1 transcription factor complex to the lmtk2 promoter. Thus, our current study has established LMTK2 as a TPA-responsive element-containing gene, which is upregulated downstream of PKC activation. Considering the involvement of LMTK2 in intracellular processes as well as pathological conditions, our findings demonstrate a way to modulate intracellular LMTK2 levels pharmacologically for potentially therapeutic purposes.

Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

“…It has been demonstrated that LMTK2 reduction is strongly associated with NFT pathology and it is not a tau-independent feature. Further studies are needed to explore the pharmacological manipulation of LMTK2-related pathways [60] as a therapeutic option in AD.…”

Unraveling the Function of Lemur Tyrosine Kinase 2 Network

“…The lmtk2 gene promoter regulates expression of endogenous LMTK2 (Dey and Bradbury, 2017). The sequence GGTGAGTCAGTG upstream of the transcription initiation site of the lmtk2 gene, conforms to the phorbol 12-myristate 13-acetate (TPA) response element (TRE) (Dey and Bradbury, 2017).…”

“…The lmtk2 gene promoter regulates expression of endogenous LMTK2 (Dey and Bradbury, 2017). The sequence GGTGAGTCAGTG upstream of the transcription initiation site of the lmtk2 gene, conforms to the phorbol 12-myristate 13-acetate (TPA) response element (TRE) (Dey and Bradbury, 2017). Exposure of HEK293, HeLa, and CFBE41o- cells to low concentrations of TPA significantly increased LMTK2 mRNA and protein levels, that were not further increased with higher concentrations of TPA.…”

Biological function of Lemur tyrosine kinase 2 (LMTK2): implications in neurodegeneration

“…Therefore, manipulation of the protein level could be a promising novel therapeutic target. A recent study has identified a 2-O-Tetradecanoylphorbol-13-acetate (TPA) responsive element in LMTK2 gene [ 110 ]. TPA is a synthetic PKC activator with ability to increase LMTK2 expression.…”

“…TPA is a synthetic PKC activator with ability to increase LMTK2 expression. The mechanism requires activator protein-1 transcription factor complex binding to LMTK2 promoter region in which the complex is trans-activated by protein kinase C [ 110 ]. These results are probably valuable but certainly not sufficient for drug development.…”