Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GADD45

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_8

GADD45 Family Members and Synonyms

Historical Background

The first GADD45 gene, now referred to as GADD45A, was originally isolated from Chinese hamster CHO-K1 cells in 1988 as a subset of transcripts that were consistently upregulated after exposure to ultraviolet (UV) radiation and several other DNA-damaging agents, including the alkylating agent methyl methane sulfonate (MMS), hydrogen peroxide, and N-acetoxy-2-acetylaminofluorene (Fornace et al. 1988). They were also found to be induced by other growth cessation signals, such as medium depletion (starvation) or hydroxyurea. This subgroup of transcripts was termed gadd, for growth arrest and DNA damage inducible (Fornace et al. 1989). GADD45A, as well as another gadd gene GADD153 (CHOP, DDIT3), was particularly interesting in that it could be induced in an ATM-dependent and protein kinase C-independent manner after exposure of human cells to ionizing radiation (IR). This induction was subsequently found to be  p53-regulated and helped define the ATM-p53 pathway; indeed, GADD45A was the first stress gene discovered that is transcriptionally regulated by p53 (Kastan et al. 1992).

There are three GADD45 proteins, which are highly homologous and encoded by three different genes: GADD45A, GADD45B, and GADD45G. GADD45B was originally cloned as a gene expressed after IL-6-induced terminal differentiation and growth arrest of M1D + myeloid precursor cells. GADD45G was similarly originally cloned as an early IL-2 response gene in T cells. These three proteins are highly conserved among metazoa, although insects have only a single GADD45 gene, which is more similar to GADD45G, indicating this may be the ancestral gene. They are all small (18 kDa), highly negatively charged (in the top two percentile of proteins in the ratio of negative charge to amino acids) and localized to the nucleus (Cretu et al. 2009). GADD45A is the most well-characterized isoform and will be the focus of this entry; the other two members will be covered more briefly.

Regulation of GADD45

A myriad of factors regulate GADD45A expression in the cell at the transcriptional, posttranscriptional, and posttranslational levels, and frequently in response to genotoxic or oncogenic stress; these are illustrated in Fig. 1 and also in Table 1. GADD45A was one of the first genes shown to be consistently upregulated after IR, across numerous conventional and gene expression profiling studies in p53 wild-type cells (Snyder and Morgan 2004). Although ubiquitously expressed, basal GADD45A expression is very low, but its expression varies through the cell cycle, with levels highest during G1 phase and lowest during S-phase (Kearsey et al. 1995).
GADD45, Fig. 1

Schematic representation of upstream regulators of Gadd45 and its downstream inducers. Arrows indicate positive regulation while blocked line indicates negative regulation. This figure is by no means a complete list of all of Gadd45’s regulators and inducers

GADD45, Table 1

A list of Gadd45’s upstream regulators. While by no means comprehensive, this table lists some of the regulators of GADD45 and whether they positively (P) or negatively (N) a particular GADD45 expression. Green letters indicate a direct transcriptional activation or repression while orange characters indicate an indirect, upstream protein-protein interaction. Red indicates posttranscriptional regulation

A well-characterized mechanism of induction of GADD45A expression is binding of p53 to a conserved site within the third intron of the GADD45A gene, stimulating its transcription. This binding is induced by genotoxic or oncogenic stress (Kastan et al. 1992; Bulavin et al. 2003), as well as during replicative senescence (Jackson and Pereira-Smith 2006). It is necessary in the GADD45A response to IR exposure but not that of UV radiation or MMS (or other base-damaging agents), although loss of p53 does attenuate subsequent GADD45A induction (Gao et al. 2009). WT1, a transcription factor that is mutated in various tumors and congenital defects, can also induce GADD45A transcription in a p53-dependent manner but in the absence of direct p53-DNA binding in response to nonionizing radiation or other genotoxic stressors (Zhan et al. 1998; Johnson et al. 2013).

A number of other tumor suppressor proteins induce GADD45A expression as well. The critical breast tumor suppressor protein, BRCA1, directly induces transcription of GADD45A after IR-exposure (Li et al. 2000; Park et al. 2008) or hypoxic shock (Maekawa et al. 2008). The mammalian forkhead family transcription factor FOXO3A binds directly to the GADD45A promoter and induces its transcription. The activating transcription factor-4 (ATF-4) plays a central role in cellular stress responses and induces GADD45A transcription in response to arsenite exposure, leucine deprivation, inhibition of the proteasome, and endoplasmic reticulum stress; however, only after arsenite exposure or proteasome inhibition did protein levels of GADD45A rise, showing that there is a sophisticated regulation of GADD45A that responds differentially to various cellular stressors (Gao et al. 2009).  Estrogen receptor β (ERβ) can bind to the promoter of GADD45A in a ligand-independent manner and recruits c-Jun and NCOA2 to stimulate transcription and subsequent G2/M arrest (Paruthiyil et al. 2011). Finally, the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors activates GADD45A expression (Tao and Umek 1999).

Mitogen-activated protein kinase (MAPK) signaling, via the c-Jun N-terminal Kinases (JNK) and p38 kinases, induces the expression of GADD45A. They activate c-Jun, which, similarly to p53, binds to the third intron of GADD45A and activates its transcription. Notably, oncogenic stress, such as constitutively elevated H-Ras or B-RAF activity, activates p38 signaling, resulting in the expression of GADD45A and oncogene-induced senescence (Bulavin et al. 2003; Jacob et al. 2011).

Transcriptional repression also takes place. The proto-oncogene c- Myc binds directly to the promoter region of GADD45A and represses its transcription (Tao and Umek 1999), highlighting the role of GADD45A in arresting cell growth. The Notch effector gene and transcriptional repressor, HES-1, directly suppresses GADD45A expression (Chiou et al. 2014), demonstrating a link between Notch signaling and GADD45A expression.

 NF-κB signaling regulates GADD45 expression through multiple mechanisms. The p65-target gene product, EGR1, directly activates the transcription of GADD45A (Thyss et al. 2005). The NF-κB-activating kinases, IKKα and IKKβ, induce GADD45A expression through a NF-κB-independent mechanism (Song et al. 2008). However, NF-κB also inhibits GADD45A expression through the activation of c-Myc and downregulation of nucleolin. Therefore, NF-κB’s differential regulation of GADD45A may contribute to the observed pro- and antioncogenic actions of NF-κB, although the mechanisms governing this switch are not well understood (Yang et al. 2009).

GADD45A is also regulated at the posttranscriptional level. In unstressed cells, AUF1 destabilizes GADD45A mRNA and TIAR1 hinders its translation. After exposure of cells to MMS or UV radiation, these proteins quickly dissociate from GADD45A mRNA and allow GADD45A protein levels to rise. Conversely, the mRNA stabilizing protein, nucleolin, binds GADD45A mRNA after cellular stimulation with arsenic chloride or inhibition of NF-κB and potently increases both mRNA and protein levels. Lastly, genotoxic stress induces the MK2 and p38 kinases to phosphorylate three proteins involved in RNA regulation, hnRNPA0, TIAR1, and PARN, stabilizing GADD45A mRNA and allowing its translation (Reinhardt et al. 2010).

The final level of GADD45A regulation is at the posttranslational level. Arsenite stimulation of cells induces the formation of an IκB-kinase-β (IKKβ)/NF-κB p50 subunit complex that decreases ubiquitinated GADD45A levels and its subsequent proteasomal degradation (Yang et al. 2009). Conversely, the ubiquitin E3 ligase MDM2 can ubiquitinate GADD45A and target it for degradation (Gao et al. 2013), consistent with a role for MDM2 in opposing p53 function.

GADD45B- and GADD45G-specific mechanisms of transcriptional regulation also exist. The p65 (RelA) subunit of NF-κB binds directly to three κB elements in the promoter of GADD45B and activates its transcription (Yang et al. 2009). Nucleus accumbens-1 (Nac1) is a transcription factor that is associated with embryonic stem cell self-renewal and pluripotency; it is also found to be upregulated in several cancer types, and particularly chemoresistant, recurring ovarian carcinomas. Nac1-mediated downregulation of GADD45G was found to contribute to paclitaxel resistance in ovarian cancer cells (Jinawath et al. 2009).

The Effects and Consequences of GADD45A Expression

As can be expected from a protein that is predominantly induced after genotoxic and other cellular stresses, the most well-characterized functions of GADD45A are to induce growth arrest and stimulate DNA repair. Although a few direct biochemical mechanisms have been shown for GADD45A, it has been repeatedly found to form complexes with other proteins and even chromatin. Thus, it seems likely that the ability to both facilitate protein-protein interactions and sequester proteins may be important; these interactions and their subsequent effects are also illustrated in Fig. 1 as well as in Table 2 for select proteins.
GADD45, Table 2

A list of Gadd45’s downstream effectors. While by no means comprehensive, this table lists some of the downstream effectors of Gadd45

GADD45A plays a role in both S- and G 2/M-phase arrest (Smith et al. 1994; Hollander and Fornace 2002); it displaces proliferating cell nuclear antigen (PCNA) from the cyclin D1 complex, inhibiting DNA replication during S-phase (Smith et al. 1994). Likewise, GADD45A can also bind cyclin-dependent kinase 1 (CDK1), preventing its association with cyclin B1, inhibiting CDK1 activity, and arresting the cell at the G2/M checkpoint (Wang et al. 1999; Hollander and Fornace 2002).

GADD45A works by multiple mechanisms to maintain genomic stability throughout mitosis. Mouse embryonic fibroblasts (MEFs) and mice with a GADD45A-/- genotype were much more likely to exhibit centrosome amplification and incomplete chromosomal condensation during mitosis. This results in defective chromosomal segregation, likely leading to the chromosomal and chromatid aberrations often seen in this genotype (Hollander and Fornace 2002), which is quite similar to the p53−/− phenotype. GADD45A physically associates with Aurora-A protein kinase, the deregulated activity of which similarly produces centrosome abnormality, and strongly inhibits it. Additionally, GADD45A and BRCA1 are both required for the full, physiological transcriptional upregulation of NEK2, the proper concentration of which has been found to be essential for timely centrosome separation (Gao et al. 2009).

GADD45A has been repeatedly associated with apoptotic induction after genotoxic stress. Its level rises notably in apoptotic mammalian cells and inhibition of GADD45A expression reduces apoptosis in response to DNA damage. c-Jun N-terminal kinase (JNK) and p38 mediate much of GADD45A’s proapoptotic effects, inducing cell cycle arrest and the apoptotic response. All three GADD45 proteins bind the N-terminus of MTK1, a mitogen-activated protein kinase kinase kinase (MAP3K) that exclusively activates p38 and JNK signaling, inducing a conformational change that resulted in its autophosphorylation, activation, and a strong apoptotic response. GADD45A activation of p38 and JNK signaling, which are upstream inducers of GADD45A expression (as well as of p53, which also induces GADD45A expression), forms the basis for a positive feedback loop to raise the levels of these tumor suppressive signaling molecules in the event of unresolved DNA damage; this positive feedback loop is illustrated in Fig. 1. Furthermore, GADD45A expression is necessary for sustained p38 and JNK signaling and consequent growth arrest or apoptosis in keratinocytes after UV radiation exposure (Gao et al. 2009).

GADD45A also effects its proapoptosis program through interaction with the cytoskeleton. Elongation factor 1α (EF-1α) is a microtubule-severing protein that binds, bundles, and promotes microtubule assembly, playing a key role in cytoskeletal stability. Interaction of GADD45A with EF-1α inhibits its bundling of microtubules, destabilizing the cytoskeleton. This causes release of Bim, a  Bcl-2 family pro-apoptotic protein, from microtubule-associated complexes and allows its translocation to the mitochondria, releasing cytochrome c into the cytoplasm and initiating apoptosis (Gao et al. 2009).

However, there does seem to be subtleties to the exact effect of GADD45A on cell survival outcomes. In hematopoietic stem cells (HSCs), it activates p38 signaling and induces their rapid differentiation (Wingert et al. 2016), and it is also a survival factor in adult rat neuronal cells after spinal ligation (Lin et al. 2011). Therefore, GADD45A functions to remove DNA-damaged HSCs by inducing their differentiation and eventual clearance. In the latter case, postmitotic neurons pose less of a risk of initiating a tumor, so this may explain the prosurvival role of GADD45A in neuronal cells.

Oncogene-induced senescence (Bulavin et al. 2003) and establishment of the senescent phenotype in response to DNA damage or aberrant oncogene signaling (oncogenic stress), as well as replicative senescence, often requires GADD45A expression (Kastan et al. 1992; Bulavin et al. 2003; Jackson and Pereira-Smith 2006; Passos et al. 2010). In both cases, GADD45A signaling through p38 was essential for induction of this phenotype and also for full transactivation of p53, the activity of which was shown elsewhere to be essential for entry of cells into a senescent state. In senescent human fibroblast cells, p53 preferentially occupied the promoters of GADD45A and CDKN1A (p21) and this was associated with a unique combination of phosphorylated p53 sites (Gao et al. 2009). Therefore, the positive feedback loop between GADD45A, p38, and p53 is essential for induction and maintenance of the senescent phenotype after oncogenic stress, DNA damage, or aging.

GADD45B and GADD45G

The other two GADD45 proteins are less well-characterized compared to GADD45A. GADD45G is clearly defined as a proapoptotic, cell cycle arrest–inducing protein (Lucas et al. 2015), similar to GADD45A. This is true for GADD45B as well to a lesser extent, although there is some controversy surrounding it. GADD45B and GADD45G inhibit CDK1 activity and play a role in S and G2/M checkpoints. GADD45B and GADD45G also activate MTK1 in order to trigger JNK and p38 signaling (Yang et al. 2009). GADD45B enhances p38 phosphorylation and activation of the retinoblastoma tumor suppressor protein (Rb) activation after Fas stimulation in murine hepatocytes (Cho et al. 2010). Similarly, a role for GADD45B in TGFβ-induced apoptosis has been shown with a genetic approach in GADD45B−/− mouse hepatocytes where this GADD45 protein was required for p38 activation (Yoo et al. 2003).

However, the role of GADD45B in apoptosis and cell growth arrest has been controversial (Amanullah et al. 2003). GADD45B has also been found to mediate NF-κB-mediated suppression of JNK-induced apoptosis by binding directly to MKK7 and inhibiting its catalytic activity (Papa et al. 2007). It also suppresses JNK signaling and subsequent apoptosis in hematopoietic cells in response to UV irradiation (Yang et al. 2009). Similarly, stimulation of CAR induces it to interact with GADD45B and cause GADD45B-mediated repression of JNK-facilitated cell death in mouse hepatocytes (Yamamoto et al. 2010). GADD45B promotes liver regeneration in vivo (Papa et al. 2008), was protective of retinal ganglion cells in the response to different neuronal injuries, such as oxidative stress, and TNFα and glutamate cytotoxicity (Liu et al. 2009), and increased neuron survival in a rat model of ischemic stroke (Liu et al. 2015).

Like GADD45A, GADD45G induces differentiation of HSCs. However, it is unclear whether this is in the context of DNA damage or cytokine signaling. Additionally, even though GADD45G mediates this effect through p38, like GADD45A, the induced lineages are restricted to megakaryocytic-erythroid cells (Thalheimer et al. 2014).

Thus, there appears to be a wide variety of roles for these two GADD45 proteins, most likely depending on the cellular context, and further characterization is necessary to determine the extent of their roles in cellular biology.

GADD45 in DNA Repair and Demethylation

Many reports have highlighted important roles for GADD45A in the DNA damage response and its ability to stimulate DNA repair. It enhances nucleotide excision repair (NER) by recruiting XPG, a component of the NER complex (Smith et al. 1994; Tran et al. 2002; Barreto et al. 2007; Rajput et al. 2016), and base excision repair (BER) through recruitment of apurinic endonuclease 1 (APE1), thymine DNA glycosylase (TDG), and the deaminase AID (Kim et al. 2013), members of the BER complex.

On the chromatin side, GADD45A can bind to acetylated or UV-irradiated nucleosomes (Carrier et al. 1999). UV photoproducts on histone-bound DNA enhances unwrapping dynamics (Duan and Smerdon 2010) and it seems that GADD45A plays a role in facilitating access of DNA damage repair proteins to DNA damaged in this manner (Carrier et al. 1999). Therefore, such evidence indicates that GADD45A is able to interact with damaged DNA/histone complexes and facilitates DNA damage repair via recruitment of DNA repair enzymes.

Additionally, there is accumulating evidence that a NER- or BER-like process is involved in removal of DNA methylation, an epigenetic marker associated with the repression of transcriptional initiation. The long noncoding RNA (lncRNA) TARID directs GADD45A to the TCF21 promoter (Arab et al. 2014), the tumor suppressor protein ING1 recruits GADD45A to tri-methylated histone 3 lysine 4 residues (Schäfer et al. 2013), and the transcription factors TAF12 and SP1 recruit GADD45A to the promoter of ribosomal genes (Schmitz et al. 2009; Rajput et al. 2016). Once recruited to the DNA, GADD45A has a role in then recruiting either the BER or NER complex to facilitate DNA demethylation (Arab et al. 2014; Li et al. 2015; Rajput et al. 2016). At least in the case of BER complex-mediated demethylation, this appears to be a two-step process: GADD45A recruits the deaminase AID to deaminate 5-methylcytosine to thymine or 5-hydroxymethyluracil. The modified residue is then repaired by BER, replacing it with an unmethylated cytosine residue, facilitating subsequent transcription (Cortellino et al. 2011).

However, in vivo studies showed significant specificity of Gadd45-mediated DNA demethylation and GADD45A- and GADD45B-null mice displayed conserved global genomic methylation patterns (Engel et al. 2009), indicating that GADD45 proteins are more likely to be involved in demethylation and transcriptional activation of specific genes. Indeed, GADD45A and GADD45B deletion (knockout) in mouse embryonic stem cells resulted in hypermethylation of only 68 specific regions (Li et al. 2015). This is not likely to be the complete list of genes of which GADD45A or GADD45B facilitates demethylation, as these two proteins have been found to contribute to epigenetic remodeling of epidermal differentiation genes (Sen et al. 2010), mechanical stress-induced genes in pulmonary artery endothelial cells (Mitra et al. 2011), and learning-associated genes in the hippocampus (Sultan et al. 2012; Jarome et al. 2015). Interestingly, the epigenetic ability of GADD45A was found to be essential for reprogramming somatic cells into embryonic stem cells (ESCs), but not for establishing the overall bimodal DNA-modification pattern in ESCs (Sabag et al. 2014). This highlights its role as facilitating demethylation of specific genes required in certain contexts, but not that of global epigenomic status. Moreover, although an epigenetic role was not investigated in the following reports, the GADD45A protein interacted directly with various nuclear hormone receptors and enhanced their subsequent transcriptional activity, including constitutive active/androstane receptor (CAR) (Tian et al. 2011), RXR α, RAR α, ER α, PPAR α, PPAR β, and PPARγ2 (Yi et al. 2000), potentially through similar epigenetic changes. Lastly, GADD45A is significantly overexpressed in CD4+ T cells from systemic lupus erythematous (SLE) patients and mediates demethylation, with subsequent increased transcription, of the promoter regions of CD11a and CD70, both of which contribute to autoimmunity and therefore progression or maintenance of the disease (Li et al. 2010), despite the role of GADD45A in T cells as a negative immune regulator (discussed below). Finally, GADD45B has been found to be required for specific DNA demethylation of factors critical for activity-induced adult neurogenesis (Ma et al. 2009). Therefore, it appears that GADD45A and GADD45B do not facilitate global epigenetic remodeling, as happens during fertilization and primordial germ cell development (Cantone and Fisher 2013), but enable demethylation of specific genes in specific cellular contexts.

GADD45 in Immune System Regulation

GADD45A has been shown to be a negative regulator of T-cell activation and proliferation. GADD45A-deficient mice, particularly females, develop a lupus-like syndrome with high titers of anti-DNA and –histone antibodies (Lu et al. 2007). Surprisingly, T cells from GADD45A−/− mice showed constitutive p38 activation, which functions via an alternative pathway to stimulate T-cell activation. Adding recombinant GADD45A to isolated GADD45A−/− T cells inhibited p38 and their hyperactivated status (Salvador et al. 2005). Similarly, the loss of GADD45A in B-cells by elevated miR-148a allows self-reactive B-cells to escape central tolerance checks and promote autoimmune disease (Gonzalez-Martin et al. 2016). Notwithstanding the heightened lymphocyte activity, Th1 differentiation in GADD45A−/− mice is impaired due to reduced expression of IL-12 and CD40 costimulatory molecule by dendritic cells (Jirmanova et al. 2007).

Despite these mechanistic observations, GADD45A expression in peripheral blood lymphocytes and monocytes from human SLE patients was actually found to be elevated, while global methylation status was significantly lower (Chen et al. 2015). As decreased global methylation status of peripheral blood lymphocytes had been previously seen in other studies (Lei et al. 2009; Liu et al. 2011), the authors hypothesized that in certain contexts, the DNA demethylation ability of GADD45A may outweigh its negative regulation of the alternative p38 pathway in T cells in pathological development of SLE.

GADD45A and B signaling is also important in the function of innate immune system cells. Granulocytes lacking the two Gadd45’s had decreased p38 activation, and macrophages higher JNK activation, following LPS stimulation. In both cases, this resulted in deficient immune cell function (Salerno et al. 2012).

Similar to GADD45A, GADD45B and GADD45G potentiate p38 signaling in Th1 and CD8+ cytotoxic T cells, which is necessary for full effector function, but are also negative regulators of T-cell activation and proliferation (Yang et al. 2001; Chi et al. 2004; Lu 2006; Ju et al. 2009). One study of GADD45B in the passive K/BxN mouse model of arthritis found that GADD45B loss exacerbated synovial inflammation, due to increased JNK signaling, and this observation was confirmed by examination of human rheumatoid arthritis synovium (Svensson et al. 2009). However, a study of collagen-induced murine arthritis found that GADD45B loss decreased arthritis severity and joint destruction, through a decrease in the ratio of pro- to anti-inflammatory cytokine production (Luo et al. 2011). This shows that loss of the same GADD45 gene in different contexts may have an exactly opposite effect. Finally, GADD45B is necessary for full expression of the Th1 lineage-inducing proteins, T-bet and Eomes (Ju et al. 2009). Thus, the GADD45 family members work in concert via multiple context-dependent mechanisms to promote full maturation and function of innate and adaptive immune cells, and to prevent inappropriate activation, except under certain pathological conditions.

The GADD45-Null Phenotype

The GADD45A-knockout murine phenotype possesses a number of deficiencies: a significant proportion of their cells display genomic instability; low levels of fetal exencephaly; and, despite wild-type levels of carcinogenesis in un-treated mice, increased rates of tumorigenesis with a shorter latency period after exposure to carcinogens such as dimethylbenzanthracene or IR (Hollander and Fornace 2002; Lu 2006). This suggests that GADD45A is more important in stress signaling and the response to DNA damage or oncogenic stress, rather than constitutive suppression of carcinogenesis. Although most mouse models using a genetic approach indicate tumor suppressor features for GADD45A, a recent report showed that it can function as a promoter or suppressor of mammary cancer dependent on the oncogenic stress (RAS- vs MYC-driven mammary cancer) (Tront et al. 2010).

Additionally, although in vitro studies have implicated GADD45A in a large number of different signaling pathways, in vivo studies generally show that the most important downstream effector of GADD45A signaling is the p38 MAP kinase pathway. Mouse models of GADD45A deficiency show that GADD45A-dependent protection against UV irradiation-induced skin tumors requires functional p38 (Hildesheim et al. 2002) and abolition of either GADD45A or p38 activity resulted in compromised negative regulation of β-catenin via the adenomatous polyposis coli destruction complex (Gao et al. 2009). Notably, full p53 activation in the sunburn response requires intact GADD45A and p38; these three proteins function in a positive feedback loop (Hildesheim et al. 2002). The tissue-specific GADD45A regulation of p38 signaling in dendritic and T cells is discussed above and highlights the importance of p38 as a target of GADD45A. Although the genomic instability exhibited by GADD45A−/− mice may be due to additional mechanisms, much of the observed phenotype seem to be mostly due to altered p38 signaling.

Involvement of GADD45 in Cancer

The GADD45 proteins have been implicated in a number of studies of cancer. GADD45A deficiency in mice resulted in increased rates of IR- or dimethylbenzanthracene-induced tumors with a shorter latency period, as discussed above. Deletion of GADD45A in an XPC−/− mouse model of lung cancer led to an increase in lung tumor malignancy, and allelic deletion of GADD45A is associated with multiple tumor types including lung (Hollander et al. 2005). Sustained ERK1/2 signaling in an acute myeloid leukemia model cell line was found to downregulate GADD45A, the reintroduction of expression of which induced S-phase arrest and apoptosis (Cretu et al. 2009). Mechanistically, simultaneous overexpression of H-ras and knockout of GADD45A were sufficient to transform cells, indicating that GADD45A knockout may serve as one of the “two hits” in oncogenic transformation (Bulavin et al. 2003).

Clinically, the GADD45A gene is rarely found to be mutated but the promoter region is methylated in a majority of breast cancers and a significant fraction of prostate cancer (Cretu et al. 2009). Its promoter methylation predicts poor prognosis in acute myeloid leukemia (Perugini et al. 2013) and aggressive, rather than benign, prostate cancer (Reis et al. 2015). Additionally, it is frequently deleted in esophageal cancers (Brown et al. 2011) and GADD45A expression is correlated with a significantly better survival rate in esophageal cancer (Ishiguro et al. 2016).

Despite the apparent tumor suppressor role of GADD45A, it also appears to offer malignant cells survival advantages, in line with its roles in cell growth arrest and DNA repair (and beyond). GADD45A expression in p53-positive tumors was significantly associated with a lower patient survival rate. GADD45A induction was also found to protect melanoma cells from UV radiationa lower patient survivalGADD45A expression in cervical carcinomas correlated significantly with a good clinical response to radiotherapy (Gao et al. 2009) and to chemotherapy in osteosarcoma cells (Yang et al. 2015), esophageal squamous cell carcinoma (Wang et al. 2012a), and gastric cancer (Lo Nigro et al. 2010). Additionally, despite decreased FOXO3A transcriptional activity, GADD45A expression was found to be upregulated in thyroid cancers (Karger et al. 2009).

The GADD45B promoter was likewise hypermethylated in several human hepatocellular carcinomas, in both cases with subsequent downregulation of expression (Qiu et al. 2004). Conversely, GADD45B expression was associated with increased relapse and patient death in human colorectal carcinoma (Wang et al. 2012b), despite the mechanistic observation that GADD45B overexpression induced apoptosis in human colorectal cancer cell lines. Finally, the pregnane X receptor can activate GADD45B/p38 MAPK signaling to induce change of morphology and migration in a hepatocellular carcinoma cell line (Kodama and Negishi 2011).

The promoter region of GADD45G was also hypermethylated and its transcription repressed in a significant number of nonsmall cell lung cancers (Na et al. 2010), lymphomas, nasopharyngeal carcinomas, cervical carcinomas, esophageal carcinomas, pituitary adenomas (Yang et al. 2009), and gastric, colorectal, and pancreatic cancers (Zhang et al. 2010). However, genetic mutation and inactivation were very rare. Exogenous reintroduction of GADD45G resulted in G2/M arrest in a number of tumor cell lines, including prostate carcinoma and pituitary adenoma (Yang et al. 2009). Accordingly, GADD45G expression is associated with a good prognosis in hepatocellular cancer (Ou et al. 2015) and esophageal carcinomas (Frau et al. 2012; Guo et al. 2013).

Given the varying reports, it seems that expression or silencing of the GADD45 proteins may be selected for based on the cellular context of the tumor. This again highlights the pleiotropic and context-dependent nature of GADD45 signaling.

Summary

The GADD45 proteins are typically characterized as classical tumor suppressors that induce cell cycle arrest and apoptosis in response to DNA damage or oncogenic stimuli. Moreover, they play important roles in a range of other physiological processes, including DNA demethylation and repair, maintenance of genomic stability through mitosis, and immunological regulation and activation, although the details and exact mechanisms of GADD45 involvement in these are still under investigation. Equally intriguing is the accumulating evidence, after initial negative findings, for a role for GADD45 in both suppressing and promoting cancer. GADD45 occupies a key role as a hub between different signaling pathways, which no doubt contributes to the difficulty elucidating its function and the contradictory reports; this is in addition to significant tissue specificity in its expression and downstream effectors. Its increased or decreased expression has been linked to cancer cell survival, chemoresistance, aggressive behavior, and migration, marking it as a possibly valuable therapeutic target or prognostic or predictive biomarker. Indeed, an inhibitor peptide that disrupts the GADD45B-MKK7 interaction selectively killed multiple myeloma, but not normal, cells (Tornatore et al. 2014). Conversely, the ability of GADD45B to specifically bind and inhibit MKK7 was exploited for development of a pharmacological inhibitor peptide that effectively protected neurons in two rat models of ischemic stroke also promoter region of ras (RAS genes) (Vercelli et al. 2015). This is a promising start for bench-to-bedside translation of GADD45 as a therapeutic target or biomarker. However, given its tumor suppressor and pleiotropic aspects, research mindful of the difficulties inherent in analyzing a key signaling molecule involved in multiple processes would be necessary to determine the most efficacious manner of exploiting it for clinical benefit.

Notes

Acknowledgments

The authors would like to acknowledge all the scientists who contributed to characterization of the role, function, and regulation of the GADD45 genes and protein products, but whose works could not be cited due to space concerns.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular and Cellular BiologyGeorgetown UniversityWashingtonUSA
  2. 2.Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA