Abstract
SummaryTranscriptional 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.
Highlights
Transcriptional co-activator with PDZ-binding motif (TAZ), referred to as WW domain-containing transcriptional regulator 1, was firstAbbreviations ADM, Adriamycin; SA-bgal, Senescence-associated b-galactosidase; TAZ, Transcriptional co-activator with PDZ-binding motif; YAP, Yes-associated protein.Accepted for publication 21 May 2017 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 deficiency caused structural abnormality and functional defects in the testis To examine the roles of TAZ in the male reproductive system, we first demonstrated that TAZ was expressed in the testis, in the spermatogenic cells of the seminiferous tubules and interstitial Leydig cells, as evidenced by immunoblotting and immunohistochemistry (Fig. 1a,b)
Further structural examination by Hematoxylin and eosin (H&E) staining confirmed that TAZ was essential for the structural maintenance because a TAZ deficiency resulted in atrophied tubules and widened interstitial spaces
Summary
Transcriptional co-activator with PDZ-binding motif (TAZ), referred to as WW domain-containing transcriptional regulator 1, was firstAbbreviations ADM, Adriamycin; SA-bgal, Senescence-associated b-galactosidase; TAZ, Transcriptional co-activator with PDZ-binding motif; YAP, Yes-associated protein.Accepted for publication 21 May 2017 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). Transcriptional co-activator with PDZ-binding motif (TAZ), referred to as WW domain-containing transcriptional regulator 1, was first. TAZ associates with various transcription factors and regulates expression of their target genes during cell differentiation and organ development (Hansen et al, 2015). 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 plays a role in cancer development because it is a key mediator of Hippo signaling. TAZ is suggested to have an oncogenic activity in human cancer such as nonsmall cell lung cancer (Zhou et al, 2011; Noguchi et al, 2014)
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