Late cornified envelope 1C (LCE1C), a transcriptional target of TAp63 phosphorylated at T46/T281, interacts with PRMT5

Norikazu Yabuta; Chie Ota; Towa Sasakura; Yoko Naito; Daisuke Okuzaki; Kohshiro Fukushima; Hiroshi Nojima

doi:10.1038/s41598-018-23045-7

Late cornified envelope 1C (LCE1C), a transcriptional target of TAp63 phosphorylated at T46/T281, interacts with PRMT5

Sci Rep. 2018 Mar 20;8(1):4892. doi: 10.1038/s41598-018-23045-7.

Authors

Norikazu Yabuta¹, Chie Ota², Towa Sasakura², Yoko Naito², Daisuke Okuzaki^{2

3}, Kohshiro Fukushima², Hiroshi Nojima^{2

3}

Affiliations

¹ Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. [email protected].
² Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
³ DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Abstract

p63, a transcriptional factor that belongs to the p53 family, regulates epidermal differentiation, stemness, cell death, tumorigenesis, metastasis, and senescence. However, its molecular mechanism remains elusive. We report here that TAp63 phosphorylated at T46/T281 specifically upregulates the late cornified envelope 1C (LCE1C) gene that is essential at a relatively late stage of epithelial development. We identified these phosphorylation sites during a search for the targets of Cyclin G-associated kinase (GAK) in vitro. LCE1C was drastically upregulated by doxycycline-dependent expression of Myc-TAp63 wild-type protein. Luciferase reporter assays using the promoter region of the LCE1C gene confirmed that the phosphorylations of TAp63-T46/T281 contributed to full transcriptional activation of the LCE1C gene. LCE1C interacted with protein arginine methyltransferase 5 (PRMT5) and translocated it from the nucleus to the cytoplasm. Mass spectrometry and co-immunoprecipitation identified importin-α as one of the association partners of LCE1C. In summary, we propose that the GAK_TAp63-pT46/pT281_LCE1C axis plays an important role in preventing the nuclear function of PRMT5.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Cell Line, Tumor
Cell Nucleus / metabolism
Cell Transformation, Neoplastic / genetics
Cornified Envelope Proline-Rich Proteins / genetics
Cornified Envelope Proline-Rich Proteins / metabolism*
Cytoplasm / metabolism
Gene Expression Regulation, Neoplastic / genetics
HEK293 Cells
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Mass Spectrometry / methods
Phosphorylation
Protein Serine-Threonine Kinases / metabolism
Protein-Arginine N-Methyltransferases / metabolism*
Protein-Arginine N-Methyltransferases / physiology
Trans-Activators / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism*
Transcription Factors / physiology
Transcriptional Activation
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism*
Tumor Suppressor Proteins / physiology

Substances

Cornified Envelope Proline-Rich Proteins
Intracellular Signaling Peptides and Proteins
LCE1C protein, human
TP63 protein, human
Trans-Activators
Transcription Factors
Tumor Suppressor Proteins
PRMT5 protein, human
Protein-Arginine N-Methyltransferases
GAK protein, human
Protein Serine-Threonine Kinases