Research Article: Transcriptional coactivator with PDZ‐binding motif is required to sustain testicular function on aging

Date Published: June 14, 2017

Publisher: John Wiley and Sons Inc.

Author(s): Mi Gyeong Jeong, Hyuna Song, Ji Hyun Shin, Hana Jeong, Hyo Kyeong Kim, Eun Sook Hwang.

http://doi.org/10.1111/acel.12631

Abstract

Transcriptional coactivator with PDZ‐binding motif (TAZ) directly interacts with transcription factors and regulates their transcriptional activity. Extensive functional studies have shown that TAZ plays critical regulatory roles in stem cell proliferation, differentiation, and survival and also modulates the development of organs such as the lung, kidney, heart, and bone. Despite the importance of TAZ in stem cell maintenance, TAZ function has not yet been evaluated in spermatogenic stem cells of the male reproductive system. Here, we investigated the expression and functions of TAZ in mouse testis. TAZ was expressed in spermatogenic stem cells; however, its deficiency caused significant structural abnormalities, including atrophied tubules, widened interstitial space, and abnormal Leydig cell expansion, thereby resulting in lowered sperm counts and impaired fertility. Furthermore, TAZ deficiency increased the level of apoptosis and senescence in spermatogenic cells and Leydig cells upon aging. The expression of senescence‐associated β‐galactosidase (SA‐βgal), secretory phenotypes, and cyclin‐dependent kinase inhibitors (p16, p19, and p21) significantly increased in the absence of TAZ. TAZ downregulation in testicular cells further increased SA‐βgal and p21 expression induced by oxidative stress, whereas TAZ overexpression decreased p21 induction and prevented senescence. Mechanistic studies showed that TAZ suppressed DNA‐binding activity of p53 through a direct interaction and thus attenuated p53‐induced p21 gene transcription. Our results suggested that TAZ may suppress apoptosis and premature senescence in spermatogenic cells by inhibiting the p53‐p21 signaling pathway, thus playing important roles in the maintenance and control of reproductive function.

Partial Text

Transcriptional co‐activator with PDZ‐binding motif (TAZ), also referred to as WW domain‐containing transcriptional regulator 1, was first identified as a phosphorylated protein that interacts with 14‐3‐3 proteins in the cytosol and translocates to the nucleus upon dephosphorylation (Kanai et al., 2000). TAZ associates with various transcription factors and regulates expression of their target genes during cell differentiation and organ development (Hansen et al., 2015). Although the interaction of TAZ with runt‐related transcription factor 2 enhances osteoblast differentiation, its interaction with peroxisome proliferator‐activated receptor γ decreases adipocyte differentiation (Cui et al., 2003; Hong et al., 2005). TAZ has also been shown to interact with the myogenic regulatory factor, MyoD, and accelerates MyoD‐induced myogenic differentiation and muscle regeneration (Jeong et al., 2010). In addition, TAZ plays key roles in regulating organogenesis of the heart, lung, thyroid, and neural crest by regulating the expression of T‐box transcription factor 5, thyroid transcription factor‐1, paired box homeotic gene 3, and members of transcriptional enhancer activator domain family (Park et al., 2004; Mahoney et al., 2005; Murakami et al., 2005; Zhang et al., 2009). TAZ also plays a role in cancer development because it is a key mediator of Hippo signaling. Hippo signaling suppresses TAZ activity through induction of TAZ phosphorylation and degradation, whereas the loss of Hippo signaling elevated TAZ activity in cancer cells, resulting in uncontrolled cell proliferation (Moroishi et al., 2015). TAZ is thus suggested to have an oncogenic activity in human cancer such as nonsmall cell lung cancer (Zhou et al., 2011; Noguchi et al., 2014).

In the present study, we first assessed the expression of TAZ in spermatogenic cells and interstitial Leydig cells in mouse testis and found that a TAZ deficiency promoted the age‐related loss of testicular functions, likely as a result of significant increases in apoptosis and cellular senescence. TAZ deficiency increased expression of the senescence‐associated proteins p21, p19, and p16, whereas TAZ inhibited p53‐dependent p21 expression and the subsequent development of senescence. Our results provided the first demonstration that TAZ was crucial for maintaining testicular structure and functions.

This work was supported by Mid‐career Research Program of the National Research Foundation of Korea (NRF‐2013R1A2A2A01068302).

MGJ and HS performed histological analysis. JHS and HJ performed in vitro assay including protein interaction and reporter assay. HKK analyzed the data and calculated statistical analysis. ESH designed the experimental plans, analyzed the data, and prepared for the manuscript for publication.

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1111/acel.12631

 

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