Following its initial identification in Japan in 1999 (Nagase et al. 1999), mitochondrial tumor suppressor 1 (MTUS1/ATIP) (2011), a putative tumor suppressor gene, has been independently identified by research groups from Japan (Kinjo et al. 2000), Germany (Seibold et al. 2003; Wruck et al. 2005), and France (Nouet et al. 2004). As a result, MTUS1/ATIP has been designated a variety of different names; therefore, the nomenclature used to describe MTUS1/ATIP in publications can be confusing.
MTUS1/ATIP was first identified in 1999 following the sequencing of 100 cDNA clones of unknown human genes from two sets of size-fractionated human adult and fetal brain cDNA libraries (Nagase et al. 1999). At this time, it was designated KIAA1288 (Genbank Accession Number: ABO33114).
In 2000, a second Japanese group independently identified MTUS1/ATIP following large-scale genomic DNA sequencing of chromosome 8p21.3 (Kinjo et al. 2000), where a loss of heterozygosity is associated with progression in a range of human cancers including breast, colorectal, hepatocellular, pancreatic, lung, and prostate cancers (Seibold et al. 2003). They designated the gene GK1 and following Northern blot analysis identified ubiquitous expression of 7.0- and 4.4-kb gene transcripts.
Then in 2003, a German group, who were investigating gene expression during induction of cellular differentiation and quiescence, using a combination of 3D collagen cell culture and differential display reverse transcriptase-polymerase chain reaction (RT-PCR), identified that MTUS1, which they designated MTGS1, was transiently upregulated during initiation of cellular differentiation (Seibold et al. 2003).
In 2004, a group at the Cochin Institute in Paris (Nouet et al. 2004) identified a 354 bp insert that encoded an open reading frame of 118 amino acids using the yeast two-hybrid cDNA cloning system and the last 52 amino acids of the human AT2-receptor as a bait to screen a mouse fetal cDNA library. This was designated ATIP-ID, which stands for interacting domain of the AT2-receptor- interacting protein. ATIP-ID interacted with the C-terminal intracellular tail of the AT2-receptor, but not with the AT1-receptor or with the C-terminal domains of other G-coupled protein receptors such as β2-adrenergic or bradykinin receptor. In total, five MTUS1/ATIP variants, which are derived from a single gene by alternate promoter utilization and exon/intron splicing, were identified. Co-immunoprecipitation studies identified a constitutive interaction between the C-terminal end of the AT2-receptor and ATIP.
Finally in 2005, a second German group independently identified an interaction between the AT2-receptor and MTUS1, which they designated ATBP50 and described it as an AT2-receptor binding protein of 50 kDa.
MTUS1 variants and the corresponding ATIP variant
Corresponding ATIP variant
MTUS1 isoform 1
MTUS1 isoform 2
MTUS1 isoforms 1 and 2
MTUS1 isoform 4
MTUS1 isoform 5
MTUS1 isoform 6
MTUS1 isoform 5/ATIP1 is the major transcript found in the brain, excepting the cerebellum (Di Benedetto et al. 2006a). Moreover, it has also been detected in organs, which contain high levels of AT2-receptor expression, such as in the female reproductive (placenta breast ovary, uterus) and the heart.
MTUS1 isoforms 1 and 2 (ATIP3) are the major transcripts found in all other organs of the body. Both transcripts show a similar pattern of distribution in human tissues; however isoform 1 is the predominantly expressed isoform in most tissues (Di Benedetto et al. 2006a).
Expression of mRNA for MTUS1 isoform 4/ATIP4 is localized to the brain, predominantly in the fetal brain, and it is particularly abundant in the cerebellum (Di Benedetto et al. 2006a). Interestingly, the cerebellum is the only region in the brain where the AT2-receptor has been consistently detected.
Although MTUS1 isoform 5/ATIP1 has been identified in the mitochondrial region of the cytoplasm (Kinjo et al. 2000; Seibold et al. 2003), only recently has the cellular localization of MTUS1 isoform 1/ATIP3a been established. Using a combination of microtubule cosedimentation assays and immunohistochemical techniques, isoform 1/ATIP3, in contrast to isoform 5/ATIP1, has been identified as a microtubule-associated protein (Rodrigues-Ferreira et al. 2009).
Full-length human MTUS1 isoform 5/ATIP1, the first isoform fully characterized by the French group, comprises 1977 nucleotides (Genbank accession number AF293357) and encodes a 436-amino acid polypeptide and shares approximately 86% homology with mouse MTUS1 isoform 5/ATIP1 (Nouet et al. 2004).
The proteins encoded by mouse and human MTUS1 isoform 5/ATIP1 are mainly hydrophilic and contain no transmembrane domains. A major component of isoform 5/ATIP1 comprises a large coiled-coil domain, which contains two leucine zippers, and a high proportion of basic residues with a stretch of 30 C-terminal residues rich in proline, serine/threonine, and arginine. Protein analysis using an antibody-specific ATIP-ID revealed four apparent molecular weights of 30, 60, 120, and 180 kDa in a range of human tissues, which are thought to correspond to the various MTUS1/ATIP homologues (Nouet et al. 2004).
All of the MTUS1/ATIP isoforms exhibit the same C-terminal domain capability to interact with the AT2-receptor (Nouet et al. 2004). MTUS1 isoform 5/ATIP1, isoforms 1/ATIP3a and 2/ATIP3b, and isoform 4/ATIP4, which correspond to murine ATBP50, ATBP135, and ATBP60, respectively (Wruck et al. 2005), share the same 3′ exons (exons 9–17) but contain differing 5′ exons (exons 8, 1, and 5, respectively). Moreover, isoforms 1/ATIP3a, 2/ATIP3b, and 4/ATIP4 are splice variants and all use exons 1, 2, 6, and 7, while in addition isoforms 1/ATIP3a and 4/ATIP4 contain exons 4 and 3, respectively.
The sequence of exon 4, which is present in human MTUS1 isoform 1/ATIP3a but not isoform 2/ATIP3b, does not exist in the coding region of either rat or mouse ATIP3, indicating that this gene, and the protein it encodes, are not present in these species (Krezel et al. 2011).
MTUS1 Function and Interaction with the AT2-Receptor
Initial studies examining the function of the most studied MTUS1 isoform, isoform 5/ATIP1, identified that recombinant expression of isoform 5/ATIP1 into MIA PaCa-2 pancreatic tumor cells, which did not endogenously express MTUS1/ATIP, inhibited cell proliferation, as measured by a 30% reduction in uptake of a thymidine analogue, bromodeoxyuridine (Seibold et al. 2003).
In 2004 it was reported, following parallel studies in wild-type monkey kidney fibroblasts (COS) cells and COS cells stably transfected with the AT2-receptor (COS-AT2), that transient transfection of isoform 5/ATIP1, into both cell lines resulted in a 50% reduction in EGF-induced ERK2 phosphorylation in AT2-receptor expressing cells but not in wild-type cells, suggesting that expression of the AT2-receptor is a necessary component of MTUS1 isoform 5 signaling cascade. Further studies, in stably transfected Chinese hamster ovary (CHO) cells, identified that overexpression of isoform 5/ATIP1 in the presence of AT2-receptors inhibited not only EGF-mediated ERK2 phosphorylation but also inhibited the effects of other growth factors, including insulin and basic fibroblast growth factor (Nouet et al. 2004). Additionally, following stimulation of isoform 5/AT2-receptor transfected CHO cells with insulin, autophosphorylation of the insulin receptor beta-chain migrating at 97 kDa was reduced compared with CHO cells transfected with an empty pcDNA3 vector (Nouet et al. 2004), i.e., it interferes at the initial step of insulin receptor signaling. It must also be noted that these studies were conducted in the absence of AT2-receptor activation, suggesting that overexpression of isoform 5/ATIP1 mimics the activation of this receptor (Elbaz et al. 2000), while only slightly modifying the expression and affinity of AT2-receptors in these cells (Nouet et al. 2004).
Further evidence supporting the possible interdependence between MTUS1 isoform 5/ATIP1 and AT2-receptor function was provided in the form of siRNA studies in N1E-115 neuroblastoma cells (Wruck et al. 2005). These studies indicated that knockdown of MTUS1 isoform 5 not only reduced the ability of AT2-receptor activation to inhibit ERK2 phosphorylation and cell proliferation, which has recently been confirmed in studies of HVEC normal human umbilical vein epithelial cells (Zuern et al. 2010), but also increased AT2-receptor expression at the endoplasmic reticulum and significantly reduced the expression of these receptors at the cell surface, indicating that the receptor was not being transported to the cell surface (Wruck et al. 2005).
MTUS1 Other Potential Signaling Partners
As identified in the previous section, the activity of MTUS1 isoform 5/ATIP1, at least, is dependent on coexpression of the AT2-receptor. Beyond this little is known concerning the intracellular interactions of MTUS1/ATIP or the mechanism by which it inhibits ERK phosphorylation. Initially it was thought that MTUS1/ATIP did not act as a phosphatase (Nouet et al. 2004) or interact directly with protein tyrosine phosphatase 1 (SHP-l), a soluble protein tyrosine phosphatase that inhibits growth factor receptor signaling. However, more recently, it has been demonstrated that following activation of the AT2-receptor, ATIP interacts with SHP-1 to induce cell differentiation in primary cultures of rat neural cells (Li et al. 2007). Moreover, the ATIP/SHP-1 complex translocates into the nucleus and increases expression of one of the ubiquitin-conjugating enzyme variants, MMS2, which prevents neural damage and enhances neural cell differentiation (Li et al. 2007).
More recently, a functional domain of MTUS isoform 1/ATIP3, designated D2, has been identified that associates with the microtubule cytoskeleton and centrosome in living cells and suppresses microtubule dynamics (Molina et al. 2013). The D2 domain also had a similar ability to isoform 1/ATIP3 to inhibit cell proliferation and in wound healing assays reduced cell migration and directionality. In addition, isoform 1/ATIP3 has been shown to directly bind with End Binding protein 1 (EB1), which is an important regulator of microtubule dynamics, independently of its interaction with microtubules (Velot et al. 2015). This interaction prevents EB1 accumulation at growing microtubule ends and is involved in reducing cell polarity.
Pharmacological Regulation of MTUS1 Activity
In PC12W rat pheochromocytoma cells, which endogenously express both the AT2-receptor and MTUS1 isoform 5/ATIP1, AT2-receptor stimulation results in a “continuous increase” in isoform 5/ATIP1 mRNA levels, which commenced 30 min following receptor activation (Wruck et al. 2005).
Similarly, poly(ADP-ribose) polymerase-1 (PARP-1), which is implicated in the development of both cardiovascular and neuronal disease, is also thought to play a role in MTUS1 gene transcription, as PARP inhibition and PARP-1 ablation suppresses MTUS1 isoform 5/ATIP1 expression and promoter activity, whereas, they increased AT2-receptor expression at the plasma membrane (Reinemund et al. 2009). These findings appear to contradict the earlier work of Wruck et al. whereby isoform 5/ATIP1 knockdown decreased AT2-expression at the cell surface and this issue remains to be resolved.
EGF stimulation has also been shown to significantly decrease MTUS1/ATIP and MTUS1 isoform 5/ATIP1 mRNA expression by 45–65% in two prostate cancer cell lines (Louis et al. 2010).
MTUS1 in Cancer
Although MTUS1/ATIP was initially thought to be ubiquitously expressed (Kinjo et al. 2000), there is now a growing body of evidence indicating that a loss or downregulation of MTUS1/ATIP mRNA expression occurs with the development of a wide range of cancers, including cancers of the pancreas (Seibold et al. 2003), ovary (Pils et al. 2005), breast (Rodrigues-Ferreira et al. 2009; Frank et al. 2007; Chanrion et al. 2008), colon (Zuern et al. 2010), bladder (Xiao et al. 2012; Rogler et al. 2014) salivary glands (Zhao et al. 2015), tongue (Ding et al. 2012; Zhao et al. 2016), and head and neck (Mahjabeen and Kayani 2016). For instance, Seibold et al. demonstrated an inverse correlation between MTUS1 mRNA expression and cellular differentiation and proliferation in pancreatic cancer cell lines and, as previously mentioned, demonstrated that recombinant expression of isoform 5 in MIA PaCa-2 cells inhibited cell proliferation (Seibold et al. 2003).
Similarly, QPCR studies examining control tissues containing ovarian tissues and cysts, 58 ovarian tumor biopsies, and 38 ovarian cancer cell lines identified that MTUS1 expression was significantly lower (P = 0.004) in primary ovarian carcinoma compared with control tissues (Pils et al. 2005).
Moreover, MTUS1 expression was also found to be significantly downregulated in cancers of the colon, compared to the corresponding normal tissues, at both the protein and mRNA level. However, no mutations in the MTUS1 coding or promoter sequences could be identified. Similarly, only five nucleotide substitutions in the MTUS1/ATIP gene were detected in 109 primary hepatocellular carcinoma tumors and cell lines (Di Benedetto et al. 2006b), suggesting that the MTUS1/ATIP gene may not be a major target for mutation in either colon cancer or hepatocellular carcinoma. By contrast, a copy number variant, which lacks exon 4 of MTUS1/ATIP (i.e., MTUS1 isoform 2/ATIP3b), has been identified in breast cancers and this variation is significantly associated with a decreased risk for both familial and high-risk familial breast cancers (Frank et al. 2007; Hinds et al. 2006).
In addition, a recent study has identified that isoform 1/ATIP3a is the predominantly altered MTUS1/ATIP isoform in invasive breast cancer and that it is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. In addition, they have demonstrated that isoform 1/ATIP3a re-expression inhibits tumor cell proliferation both in vitro and in vivo and its overexpression delays the progression of mitosis by extension of the metaphase (Rodrigues-Ferreira et al. 2009).
Studies in human prostate cancer cell lines that express functional AT2-receptors (Chow et al. 2008) indicate that in a model of early stage, androgen-dependent prostate cancer, LNCaP cells, in which MTUS1/ATIP expression was knocked down using siRNA techniques the ability of EGF to stimulate DNA synthesis was potentiated, whereas it had no effect on the basal rate of DNA synthesis. By contrast, MTUS1/ATIP knockdown in a model of late-stage, androgen-independent, prostate cancer, PC3 cells, resulted in a significantly increased basal rate of thymidine incorporation and stimulation of the cells with EGF did not increase DNA synthesis beyond this already heightened level of activation (Louis et al. 2010). Further studies examined the transient overexpression of MTUS1 isoform 5/ATIP1 in PC3 cells, as it expresses relatively low endogenous levels of ATIP. In these studies not only the basal rate of ERK2 phosphorylation was diminished but the ability of EGF to stimulate this pathway was also attenuated (Louis et al. 2010).
Of particular interest in prostate cancer however, is the re-expression of MTUS1/ATIP in the neoplastic epithelial cells in high-grade prostatic intraepithelial neoplasia, the premalignant phase of prostate cancer (Louis et al. 2007), suggesting that the downregulation of MTUS1/ATIP expression identified in other cancers may be preceded by an initial re-expression early in the malignant process, which may be of value in diagnosing the premalignant stage of a number of cancers in particular prostate cancer (Louis et al. 2011).
MTUS1 in Other Disease States
Recent reports indicate that MTUS1/ATIP may inhibit growth factor signaling not only in cancer but in other disease states characterized by excessive growth. For instance, the MTUS1/ATIP variants are abundantly expressed in cultured cardio-myoblast and myotubules and there is evidence to suggest that isoform1/ATIP3A may play an antiproliferative and antihypertrophic role in these cells in the absence of AT2-receptor expression or activation (Varghayee et al. 2015). Further evidence that supports a role for MTUS1/ATIP in the development of cardiac disease comes in the form of a report which describes the development of MTUS1 knockout mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. In these animals 28% developed cardiac hypertrophy and 12% developed nephritis, independent of blood pressure levels (Zuern et al. 2012).
Other studies indicate that MTUS1/ATIP may play an important role in adipocytes as there evidence suggesting that this protein may exert anti-inflammatory effects in adipose tissue via macrophage polarization (Shinoda et al. 2015) and that it may be required for beige adipocyte differentiation and thermogenic function (Jing et al. 2013). In addition, a quantitative proteomic study identified that MTUS1/ATIP was one of the six proteins upregulated following hyperoxia in rat kidney; however, the role of MTUS1 in this process is still to be elucidated (Hinkelbein et al. 2015).
MTUS1/ATIP is a putative tumor suppressor gene, which localizes at 8p22 and encodes a family of five proteins as a result of alternate promoter utilization and exon/intron splicing. All five proteins contain a C-terminal domain which can interact with the AT2-receptor. MTUS 1 isoform 1/ATIP3a is the predominantly expressed variant throughout the body, excepting the brain where isoform 5/ATIP1 is the major transcript. The subcellular localization of MTUS1 isoform 1/ATIP3a has only recently been identified in the microtubules of SK-MES, HeLa, RPE1, MDA-MB-231, and MCF7 cells, whereas isoform 5/ATIP1 has been identified in both the mitochondria and Golgi matrix. Relatively little is currently known concerning the action of MTUS1/ATIP; however, isoform 5/ATIP1, the most studied variant to date, has been shown to inhibit growth factor-induced ERK2 phosphorylation and cell proliferation in both normal and cancer cell lines, possibly by acting directly on growth factor receptors or via interaction with SHP-1. By contrast, separate domains of isoform 1/ATIP3A have been shown to associate with either microtubules or directly bind with EB1, thereby suppressing microtubule dynamics; inhibiting cell proliferation, migration, and directionality; and reducing cell polarity. Studies indicate that MTUS1 isoform 5/ATIP1 and isoform 1/ATIP3a are downregulated in a range of human cancers and a mutation in isoform 1/ATIP3a has been associated with a decreased risk for both familial and high-risk familial breast cancers. More recently, evidence has emerged that ATIP/MTUS1 may also play an important role in other tissues, such as the heart, fat, and the kidney. Although there is much to be learned regarding the function and signaling pathways of MTUS1/ATIP, the information available indicates that it may play an important inhibitory role in cell proliferation and therefore may prove a potential therapeutic target in not only cancer but also other disease states characterized by excessive growth.
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