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AP-1: Its Role in Gastrointestinal Malignancies

  • P. S. Sushma
  • P. UdayKumar
  • Aliya Sheik
Chapter

Abstract

The role of transcription factor AP-1 (activator protein 1) in human physiology is distinct due to its involvement in tissue regeneration in which the metabolism is instigated by the signals which trigger undifferentiated proliferative cells to proceed toward cell differentiation. Consequently the functions of AP-1 may be altered in response to extracellular signals. The studies on gene-knockout mice and AP-1-deficient cell lines propose that AP-1 regulates multiple gene targets and accomplishes accurate physiological functions. There is a significant breakthrough in unveiling the molecular mechanisms and signaling pathways that monitors AP-1 activity. AP-1 functions as a double-edged sword in cancer progression through monitoring gene expression involving cell proliferation, cellular differentiation, cell death, and tumor invasion. AP-1 can be oncogenic and antioncogenic too. The activities of AP-1 in cancer appear to rely on composition of AP-1 dimers and type, stage, and genetic basis of cancer. c-Jun protein, one of the subunits of AP-1 up on activation, is expressed primarily at invasive front in carcinomas leading to the proliferation of malignant cells. Thus, c-Jun mainly has oncogenic functions, while JunB and JunD have antioncogenic effects. AP-1’s role is being studied not only in cancers but also in disorders such as psoriasis, asthma, and transplant rejection. AP-1 emerged as drug discovery target in recent years. This review is being structured to highlight the role of AP-1 transcription factor in the gastrointestinal malignancy progression.

Keywords

AP-1 transcription factor c-Jun c-Fos Cell proliferation Cellular differentiation Apoptosis Gastrointestinal cancers 

3.1 Introduction

Cancer is an out-of-control proliferation of particular cell type originating with an undesirable mutation, which results in aggregation of abnormalities in many classes of genes. The proto-oncogenes accelerate the cell cycle, and the tumor suppressor genes control the cell growth. The signal transduction pathways along with two stress response pathways act as molecular circuits found to be highly conserved in all the vertebrates. The transcription factors are the proteins that participate at the endpoint in signal transduction pathways resulting in alteration of specific genes. Most of the cancer-causing genes participate in these pathways by transferring the exogenous and endogenous signals at the cellular level. Tumor progression can be due to the cross talk between the healthy cells, loss of communication in between cancer-causing genes, abnormal DNA methylation status, hypermutability, and genetic instability. Cancer has multifaceted etiology, a large number of defects in thousands of genes leading to pernicious disease. Transcription factors execute distinct transcription programs. The activator protein 1 (AP-1) may be referred to as a matrix of transcription factors which functions throughout the trajectory of tumor progression. This perspective outlines the current perusal of changes in AP-1 and its role in gastrointestinal malignancies which includes carcinoma of the liver, pancreas, esophagus, stomach, and gallbladder and colorectal cancers.

AP-1 is a transcription factor that has a heterodimer structure made up of protein molecules belonging to families JDP, ATF, c-Fos, and c-Jun. AP-1 monitors diverse cellular processes which include cellular differentiation, cell growth, cell proliferation, and apoptosis or programmed cell death (Fig. 3.1) [1]. It was discovered as TPA-activated transcription factor bound to a cis-regulatory unit of human metallothionein IIa promoter and SV40. The AP-1 binding site was distinguished as the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE) with 5′-TGA G/C TCA-3′ as consensus sequence [2, 3]. Jun (the subunit of AP-1) and Fos-associated p39 protein were identified as an oncoprotein of avian sarcoma virus and the transcript of cellular Jun gene, respectively. Wagner reported that Fos is a cellular homologue of two viral v-Fos oncogenes (which induces osteosarcoma in rats and mice) [4].
Fig. 3.1

Mechanism of AP-1 transcription factor in cellular process.The growth factors stimulating c-Fos resulting in cell growth and proliferation via AP-1 activation. AP-1 modulating gene expression leading to cell differentiation. Extracellular matrix and genotoxic agents induce AP-1 activity resulting in apoptosis

AP-1 is reported to regulate the expression patterns of target genes in reciprocation with external stimuli like stress, cytokines, growth factors, and viral as well as bacterial infections [5]. The AP-1 activity is in turn regulated by means of posttranslational modifications, by its DNA-binding dimer composition and also mainly their interaction within different binding partners. Right from the time of discovery, AP-1 is associated with many physiological functions (principally in determination of life span of an organism and in tissue regeneration process) as well as regulatory processes, while some of its novel functions are still under investigation.

The AP-1 subunits, c-Fos and c-Jun, form dimers and play a crucial role in cell growth and cellular proliferation. Hence, the activation and functions of AP-1 are primarily determined by critical patterns of the AP-1 dimers [1]. The AP-1 subunits may bind to the palindromic DNA motif (5′-TGA G/C TCA-3′) in order to modulate the target gene expression, but specificity depends on the composition of dimers of corresponding bZIP subunit [1]. The role of c-Jun is imperative for fibroblast proliferation [6], and both the subunits were expressed above the basal levels in the course of cell division [7]. The expression patterns of c-Fos increase in reciprocation with the introduction of growth factors into the cell, besides strengthening its evocative participation in cell cycle. IL2, TGF-α, and TGF-β-like growth factors were displayed to invigorate c-Fos and reinforce the process of cellular proliferation by activating AP-1 subunits.

Several systems proposed the involvement of AP-1 in cellular differentiation. AP-1 was reported to participate in synchronizing the expression of target genes. The alterations in gene expression at cellular level reflect the DNA synthesis initiation resulting in the generation of differentiated derivatives which in turn leads to cellular differentiation. In a study on chicken embryo fibroblasts (CEF), it has been proved that when AP-1 is formed by stable heterodimers with c-Jun, the bZIP region of the v-Fos enhances the binding potential of the transcription factor to the target genes through c-Jun; this activation intiates differentiation of CEF [8].

AP-1 and its association with apoptosis is widely identified. Its mechanism is instigated through several genotoxic agents and extracellular matrix proposing their participation in apoptosis [1]. The c-Jun N-terminal kinases (JNKs) are triggered by these stimuli resulting in Jun protein phosphorylation and increased transcriptional activity of genes dependent on AP-1 [1]. Increased range of JNK activity and Jun as well as Fos protein levels was reported in cells where apoptosis has taken place. Few studies reported cells of inactivated c-Jun-ER showing general morphology, whereas c-Jun-ER activated cells are apoptotic [9]. Increased levels of AP-1 lead to the activation of target gene expression. Thus, the regulation of activity of AP-1 is crucial for cell function which is monitored by events such as posttranscriptional and posttranslational events and dimer composition as well as their interaction with respective accessory proteins [10].

AP-1 is known to play a vital role in physiology of the skin along with tissue regeneration. The metabolism is instigated by extracellular signals which set off undifferentiated proliferative cells and undergo cellular differentiation. Thus, the AP-1 subunit activity in response to the extracellular signals can be modified under circumstances when the balance of keratinocyte proliferation as well as differentiation has to be temporally and rapidly altered [11]. Earlier studies reported the involvement of AP-1 in the growth of breast cancer through multiple mechanisms, which include regulation of the genes downstream to E2F and cyclin D1 expression regulation, and their target genes. The AP-1 subunit, c-Jun, was proved to regulate the breast cancer cell growth. The activated c-Jun is known to be mostly expressed at the invasive front in squamous breast cell carcinoma and is said to be prominently linked with breast cell proliferation [12].

3.2 AP-1 and Hepatocellular Carcinoma

The liver secretes bile juice which can break down the fat consumed in food to ease absorption. These fats are being processed along with some proteins which play an important role in clotting of blood. In addition the liver processes alcohol, toxins, poisons, and some medicines to flush them out of the body. The liver malignancy, which is diagnosed in 500,000 cases annually as hepatocellular carcinoma (HCC), is the third most common cause of cancer deaths in the world [13]. The major risk factors of HCC are consumption of alcohol and infections due to hepatitis B and hepatitis C [14]. The incessant intrahepatic inflammation due to infections maintains a balance in the cycle of cell (liver) destruction and regeneration which often ends up in HCC [15, 16]. To examine the molecular mechanisms behind HCC progression in different stages, a wide range of mouse models were developed [17] which imitate the etiology of hepatocellular carcinoma in man. HCC may be due to DNA damage induced in hepatocytes by external chemical carcinogens. When mice are injected with diethylnitrosamine (DEN), a tumor initiator, they can develop liver cancer [18, 19]. Inflammation also plays a promising role in liver cancer progression [20, 21].

AP-1 transcription factors identified near the receiving ends of numerous signaling pathways are made up of homodimers or heterodimers of leucine zipper (bZIP) protein family [4].The functions of AP-1 protein were established through experimental mice model in which the functional manipulation of bZIP proteins was studied. Johnson and his co-workers suggested that c-Jun disruption in mice model resulted in embryonic lethality during midgestation. The embryos evidenced cardiovascular imperfections and impaired liver development [22]. HCC development was completely inhibited in the DEN liver cancer model (c-Jun knockout in the liver of an adult mice), thus demonstrating the importance or prominence of c-Jun in liver cancer progression [23]. Smeal and co-workers’ study has shown that c-Jun coordinates with Ha-Ras during normal cell transformation to cancer cell [24].

Multiple studies demonstrated the role of JDP2 in malignant cell transformation and inhibit AP-1 transcription by interfering with the c-Jun oncogenic properties. JDP2 is implicated in cell differentiation like differentiation of skeletal muscle cell [25] and osteoclasts [26] in stress response to ultraviolet irradiation [27]. JDP2 prevents cellular transformation influenced by Ras in vitro and also in xenografts implanted into SCID mice [28]. In some studies, in mice model with viral insertional mutagenesis, JDP2 was identified as a candidate oncogene in high-throughput screening. Several gene expression studies noticed the increased levels of JDP2 in cancers of the kidney, skeletal muscle, liver, and prostate. Transgenic mice were developed with liver-specific expression of JDP2 and chemically induced cancer hepatocellular model to examine/investigate the involvement of JDP2 increased expression in hepatocellular carcinoma. It was proved that increased JDP2 expression enhanced liver cancer severity.

3.3 AP-1 and Pancreatic Cancer

The pancreas, a flat pear-shaped gland with both exocrine and endocrine function, is located in the abdomen. It is both an exocrine and endocrine gland. The exocrine cells help in digestion, while the endocrine cells of the pancreas help in blood sugar regulation. The lining of the pancreatic duct usually divides more rapidly than the normal cells; thus, there are more chances for an abnormal cell to develop, which divides abnormally and can spread inside the pancreas and then to the nerves and the blood vessels around the pancreas bringing about blockage in the bile duct. Pancreatic cancers mainly spread through the blood as well as through the lymphatic system to other organs of the body.

Signaling pathways as well as their transcription factor targets may be dysregulated in pancreatic ductal adenocarcinoma (PDAC) [29]. The determined activation of the two main transcription factors, nuclear factor-κB (NF-κB) and AP-1, is a characteristic of cancer. Despite the fact that NF-κB was extensively studied [30, 31], very little information is available on AP-1 in PDACs. The AP-1 protein is a dimeric complex (homodimer and heterodimer) composed of Jun (Jun, JunB, and JunD) and Fos (Fos, Fra1, Fra2, and FosB) families, activating transcription factor subfamily (Atf and Creb), and Maf subfamily. Each complex can be functionally defined in determining the certainty of the genes being regulated [32, 8]. AP-1 complexes which bind to palindromic DNA sequences are interpreted as TRE or cARE (cyclic AMP response elements) in promoters as well as enhancers of c-Jun and other target genes [23, 33]. The genetic deletion of c-Jun, JunB, or Fra1 may lead to the embryonic lethality in mice model because of abnormal organogenesis. c-Fos and c-Jun were initially discovered as viral oncoproteins, which are implicated in bone, skin, and liver carcinogenesis. Hezel and co-workers reported that c-Jun is found to be overexpressed in Hodgkin’s as well as anaplastic large cell lymphoma and may increase oncogenic Ras-mediated cell transformation [29, 34]. c-Jun and c-Fos might be overexpressed because of an epidermal growth factor receptor-mediated autocrine pathway in PDACs [35, 36, 37, 38]. In comparison with c-Fos, FosB, and c-Jun, the AP-1 proteins Fra1, Fra2, JunB, and JunD may have poor transactivation potential and with less or without transforming activity. However, the overexpression of Fra1 and Fra2 in mice induced tumors in different organs which include the pancreas suggesting that they are dimerized with AP-1 proteins which have more potent transactivation domains. JunB and c-Jun have overlapping developmental functions; JunB may be a tumor suppressor which antagonizes the tumorigenic potential of c-Jun [8, 23]. A study reported that Rap1, a Ras antagonist, with the increase in transforming growth factor-β type II receptor expression through a JunB-dependent pathway, reduces the tumorigenicity of pancreatic tumor cells. The regulating ability of c-Jun in cellular proliferation, survival, and cell death may contribute to counteracting its roles in development and tumorigenesis. Thus, the mouse fibroblasts of c-Jun are proliferation defective, and liver regeneration is damaged without c-Jun [39]. c-Jun is considered essential for cell survival in the livers of fetal mice and is also required for apoptosis [4041]. c-Jun’s ability to induce apoptosis mediators called Fas L and Bim and transcriptionally repress tumor suppressors such as p53 may explain these opposing roles [8]. The activity of AP-1 is not only regulated by dimer composition but also by other mechanisms. Interactions with NF-κB and MPK (mitogen-activated protein kinase) or PI3K (phosphoinositide 3-kinase) signaling pathways [42, 43] may be critical for AP-1 function in pancreatic cancer cells. In comparison with c-Jun, NH2-terminal kinase (JNK) controls c-Jun transcription via phosphorylation of Ser63 and Ser73, and PI3K and its protein kinase mediator Akt may regulate AP-1 at various levels. There are evidences that Akt induces c-Fos and Fra1 expression and also it may suppress the phosphorylation of c-Jun (Thr239) via glycogen synthase kinase-3 (GSK-3) in order to stabilize it [44, 45], [46, 47, 48, 49]. Feedback loops may be involved because c-Jun can activate Akt and enhance proliferation and survival in cells through Ras stimulation or suppression of the PI3K antagonist PTEN [50, 51]..Although JNK and AKT may interact through the ASK, POSH, and JIP1 proteins, they are known to use distinct mechanisms to regulate c-Jun. When compared with JNK [52], still there is a controversy regarding the role of Akt in pancreatic cancer cells. It was earlier studied that AKT and P13K are activated in pancreatic cancer cells because of aberrant PTEN expression as well as insulin receptor substrate-1-mediated signaling [53, 54]. Shun and his co-workers identified the probability of activation in these cells which is regulated by the PI3K signaling pathway. Their inference shows that different AP-1 proteins are expressed in pancreatic cancer cells; c-Jun is imperative for their proliferation and is regulated by Akt signaling through transcriptional activity independently of Thr239 and Ser63/Ser73, the phosphorylation sites regulated by GSK-3 and JNK, respectively.

3.4 AP-1 and Esophageal Cancer

The esophagus or in simple terms the food pipe transfers food from the mouth to the stomach. The cancer can develop throughout the length of esophagus. Glands around esophageal walls produce mucus which helps food to slide down after swallowing. These mucous glands may turn out to be carcinogenic and develop adenocarcinoma of the esophagus, one of the frequent cancers. Other cancer types include squamous cell carcinoma.

Esophageal cancer is known to be one of the most virulent malignancies, ranking eighth in incidence and sixth in mortality rate globally [55]. These neoplasms are particularly incident in China and few other countries in Asia, where esophageal squamous cell carcinoma (ESCC) is the most prevalent [55]. A 5-year overall survival rate was not improved evidently despite the progressed surgical techniques and new therapeutic approaches in the past few decades [56]. Adjuvant chemotherapy for ESCC may reduce postoperative recurrence as well as improve survival [57]. Evidences report that the cancer often acquires resistance through chemotherapy after the nonlethal exposure [56, 58]. Thus an integrated view of chemoresistance can provide a more valuable approach for developing novel therapies for this disease.

ID1 belonging to the helix-loop-helix (HLH) protein family contributes to cancer by counteracting cellular differentiation and stimulating cell proliferation as well as enabling tumor neoangiogenesis [59]. ID1 was known to be overexpressed in multiple human tumor types which include breast, colon, prostate, and esophagus. The overexpression of ID1 is most common in human primary ESCC. ID1 expression directly correlates with tumor invasion and metastasis as well as poor prognosis in esophageal cancer patients [58, 60, 61]. It was known that ID1 was involved in radiotherapy resistance and chemotherapy resistance in human cancers like breast cancer, pancreatic adenocarcinoma, colorectal cancer, lung cancer, and esophageal cancer which becomes a novel potential therapeutic target [62, 63, 64]. ID1 is transactivated in the 5-FU therapy, which can provide a resource for the future study directing the molecular mechanisms of chemotherapy in breast cancer patients. In a study of p53 protecting cells from cell cycle arrest caused by arsenic, ID1 is extensively induced by arsenite in p53-proficient cells than p53-deficient cells, which show greater resistance to arsenite-induced apoptosis and mitotic arrest [65]. According to recent study, the competitive binding degeneration and thymidylate synthase expression take place to stimulate chemoresistance among esophageal cancer patients. The ID1-E2F1-IGF2 regulatory axis has prominent implications for cancer prognosis as well as treatment options. It is indicated that ID1 is upregulated by chemotherapeutic drugs and can be involved in chemoresistance although the mechanisms of ID1 affecting chemoresistance are yet to be investigated.

AP-1 is a menagerie of dimeric basic region-leucine zipper (bZIP) proteins which are identified either as TRE (5′-TGAG/CTCA-3′) or cARE (CRE, 5′-TGACGTCA-3′) [5]. AP-1, a mammalian transcription factor, collectively illustrates a group of functionally as well as structurally related members of Jun protein family and Fos protein family [5]. Previously it was reported that AP-1 is involved in multidrug resistance along with cell survival [66, 67]. Recently researchers demonstrated that aberrantly high levels of ID1 expression in neoplasms are due to induction of transcriptional activity by several proteins that are activated in a constitutive way among cancerous cells and affect the chemoresistance in patients [68, 69]. Identifying the important roles of ID1 and AP-1 in chemoresistance as well as transcriptional regulation between these ID proteins and AP-1 is a challenge to be addressed.

According to earlier studies, ID1 communicated etoposide chemoresistance via inhibiting caspase 3 activity and PARP cleavage, and etoposide-induced apoptosis was promoted via ID1 ablation. Spontaneously c-Jun/c-Fos can bind directly to the ID1 promoter region and activate its transcription in vivo. Ectopic expression of c-Jun/c-Fos enhances ID1 transactivation. Contrarily knockdown of c-Jun/c-Fos prevents ID1 transactivation. Overexpression of ID1 retrieves cells from apoptosis in c-Jun/c-Fos knockdown cells. The expression levels of ID1 are positively correlated with c-Jun/c-Fos in human cancers. More significantly analysis of the gene expression profiles of different cancer types indicated that high expression of ID1 and c-Jun or c-Fos may be associated with poor survival rate among patients. These findings suggest that c-Jun/c-Fos is involved in the chemosensitivity mechanisms and they contribute to the regulation of ID1 with response to chemotherapeutic drugs instigating apoptosis.

AP-1 may transcriptionally regulate ID1 in response to DNA damage thus causing chemoresistance to therapeutic drugs in ESCC cells. ID1 expression may be directly correlated with c-Jun and c-Fos in majority of malignancies. More predominantly, high ID1 and c-Jun/c-Fos expression levels in human neoplasms are significantly correlated with shorter survival rates among cancer patients. In addition they demonstrated the prominence of c-Jun/c-Fos-ID1 signaling pathway in chemoresistance of esophageal cancer cells. This study provides an insight in targetting c-Jun/c-Fos-ID1 for cancer therapeutic strategies. Moreover their results evidence the importance of developing novel anticancer therapies and pathways in understanding the unrevealed mechanisms among ESCC cell studies.

3.5 AP-1 and Gallbladder Cancer

Gallbladder (GB) malignancy is quite a rare tumor of the biliary tract especially in Western societies and Asia-Pacific countries including Korea, Australia, and Japan. In 2011, among 771 Australians, half of the patients were diagnosed with gallbladder cancer and other half with biliary tract cancer. Majority of patients with these cancers were diagnosed in later stages where the tumor becomes too large to be removed surgically.Only one fourth of gallbladder cancer patients were reported to be eligible for surgery.The survival rate of these patients is very low still. According to the reports, the average 5-year survival rate for these patients is only 18.5%. For the patients who are not eligible for surgery, chemotherapy remains the other treatment option. At present, there are no prescribed chemotherapy regimens for GB cancer that was shown to specifically help patients to survive longer.

In gallbladder patients, tumor necrosis factor-alpha (TNF-α) was identified to play an important role in lymphatic metastasis. Vascular endothelial growth factor-D (VEGF-D) is another factor considered to be associated with lymph node metastasis and lymphangiogenesis. However VEGF-D’s role in TNF-α-induced lymphatic metastasis in GB cancers remains unknown. The TNF-α levels are correlated with VEGF-D expression in clinical specimens. According to earlier studies, the effects of TNF-α are due to multiple signaling pathway activations in combination with TNF-α and its receptors (via NF-κB or AP-1 pathway). The two binding sites in VEGF-D promoter core region reveal that the upregulation of VEGF-D is through the AP-1 pathway. TNF-α upregulates the expression of protein as well as promoter activity of VEGF-D via ERK1/2/AP-1 pathway. Additionally TNF-α promotes HDLEC tube formation and lymph node metastasis among GBC patients by upregulating VEGF-D in vivo and in vitro. So considerably it suggests that TNF-α may promote lymphangiogenesis and lymphatic metastasis of GBC via ERK1/2/AP-1/VEGF-D pathway.

The studies by Schafer and Ming suggested that HNF-4α (hepatocyte nuclear factor 4α), COUP-TF1 and COUP-TF2 (chicken ovalbumin upstream promoter transcription factors 1 and 2), and AP-1 bind to VEGF-D promoter, [70]. Multiple transcription studies demonstrated that NF-κB or AP-1, [71] is associated with tumor progression. TF bind and promoter scan were used to determine the potential binding sites of NF-κB or AP-1 in the VEGF-D promoter having three fragments with higher activities. Eventually, it is confirmed that both the AP-1 sites can bind to the VEGF-D promoter and that TNF-α might enhance the combination by site-directed mutagenesis.

3.6 AP-1 and Gastric Cancer

The stomach receives and stores food from the esophagus. Ingested food is passed from the stomach to the small intestine where nutrients are absorbed into the bloodstream. Majority of gastric cancers develop within the cells of mucosa resulting in adenocarcinoma of the stomach. Gastric cancers develop steadily and take several years before the onset of symptoms.

The activity of c-Jun is augmented in several tumor types, but its role in gastric cancer is largely unknown. The aminoterminal phosphorylation of c-Jun by JNKs shows that the phosphorylation-dependent interaction between c-Jun and TCF4 regulates intestinal tumorigenesis by integrating JNK and APC/beta-catenin.These two distinct pathways are activated by Wnt signaling [72]. It was proposed by Wong and colleagues that a COX-2 inhibitor suppresses AP-1 via JNK in carcinoma of the stomach. Earlier studies reported c-Jun positivity in a large number of gastric cancer patients.

3.7 AP-1 and Colorectal Cancers

Colorectal cancer is sometimes referred to as bowel cancer. The bowel connects the stomach to the anus taken together with the large colon and rectum. The bowel usually develops small growths called polyps which appear like tiny dots near the bowel lining. However, all the polyps are not cancerous.The early detection of polyps in the colon or rectum may reduce the risk of colorectal cancers.

AP-1 functions to regulate gene expression in conjugation with multiple stimuli and is also involved in multiple cellular processes, such as differentiation, proliferation, and apoptosis, like other gastrointestinal cancers [1, 5]. Various genes may encode the monomers of the AP-1 complex. These transcription factors play a crucial role as they are located downstream to many transduction pathways. The hallmark of CSC phenotype is interpreted by several genes; however, NANOG, POU5F1 (OCT3/4), and SOX2 have prominent roles [73].

Recent experimental studies indicate that c-Jun is salient for the maintenance of self-renewal as well as tumorigenicity of glioma stem-like cells [74]. Another study reports that in colon cancer c-Jun and TCF4 stimulated a subpopulation of colorectal cancer tumor cells to endorse a stem-like phenotype through the NANOG promoter [75]. Furthermore c-Fos enables to continue hematopoietic stem cells in the quiescence [76]. Panagiotis Apostolou and colleagues focused at demonstrating the association between the AP-1 complex and the stemness transcription factors. They addressed whether the AP-1 transcription factor is required to activate or suppress NANOG, OCT3/4, and SOX2 transcription factors and also whether it has an effect on apoptosis and cell cycle events.

c-Fos which is a proto-oncogene has a leucine zipper DNA-binding domain. c-Jun is also a proto-oncogene which has got important roles in cellular proliferation and cell death [77]. The AP-1 transcription factor operates downstream of multiple transduction pathways; thus various processes were implicated. Few studies have elaborated that c-Jun and c-Fos may be involved in the stemness pathways. c-Jun has a crucial role in the maintenance of self-renewal as well as tumorigenicity in glioma stem-like cells. In contrast a study has detailed that AP-1 and NF-B induce differentiation of mouse ESCs [66, 74, 78].

Thus there exists an association between AP-1 and stemness. The AP-1 has its contributions in apoptosis, along with that of individual proteins. AP-1 appears to deliver a central role in balancing stemness through monitoring OCT3/4, SOX2, and NANOG. Repression of AP-1 leads to NANOG level reduction as well as expression of SOX2 gene, which in turn may lead to an increase in cells encountering apoptosis. The cells which are unable to conduct stemness undergo apoptosis.

The recent studies evidence that AP-1 could be potentially associated with the stemness phenotypes in colorectal squamous cell carcinomas. The decrease of its expression may lead to changes in expression of the major transcription factors which are requisites for balancing pluripotency as well as undifferentiation. Additional studies are required to investigate this association further.

3.8 Conclusion

Advances in the field of gene regulation have commenced to discover the transcriptional networks which are operated in the neoplastic cells. These approaches in research offered insights into transcriptional regulatory molecules that can be targeted to rectify irregular gene functions. An accurate survey on signaling networks that are involved in oncogenic transcription factors can provide up-to-date features in transcription that has to be addressed. Advanced, structure-based minute drug molecules with minimum side effects and high selectivity can be generated in the future basing on the transcription factors instrumental in cancer formation. The mechanisms contributing to AP-1 activity regulation and its gene targets whose expression has to be regulated by AP-1 are still under investigation. Few mechanisms were disclosed such as modulation of transcription factor activity by protein phosphorylation and methodology used by cell surface receptors to interface nucleus. Forbye the recognition of critical AP1 gene targets can divulge the activities of AP1. One of the major challenges to be tackled in cancer biology is comprehending the probable mechanisms that confer the actions of protein kinases and transcription factors. The generic and ubiquitous signaling proteins like components of AP1 may be involved in immensely specific biological responses.

Notes

Acknowledgments

Authors are grateful to the Dr. NTR University of Health Sciences and National Institute of Nutrition (ICMR) for their encouragement.

Conflict of Interest

None declared.

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Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  1. 1.Dr. NTR University of Health SciencesVijayawadaIndia
  2. 2.National Institute of Nutrition (ICMR)HyderabadIndia
  3. 3.Jawaharlal Nehru Technological UniversityHyderabadIndia

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