Mol. Cells 2018; 41(5): 381-389
Published online April 18, 2018
https://doi.org/10.14348/molcells.2018.0100
© The Korean Society for Molecular and Cellular Biology
Correspondence to : *Correspondence: jso678@yonsei.ac.kr
ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the
Keywords ARF, E3 ligases, post-translational modification, transcriptional regulation, tumorigenesis
Uncontrolled cell proliferation is the one of the hallmarks of cancer. Aberrant growth signals or oncogenic stimuli including RAS or c-MYC elicit hyper-proliferation of cells. These processes are normally blocked by a primary fail-safe program including senescence, which is an irreversible cell cycle arrest that restrains aberrant tumor progression (Collado and Serrano, 2010; He and Sharpless, 2017; Lindstrom and Wiman, 2003; Serrano et al., 1997; Zindy et al., 1998). Bypass of the fail-safe program allows cell transformation, with progression of tumorigenesis in normal cells (Brown et al., 1997; Chen et al., 2005; Eischen et al., 1999). The expression of the
The
A fundamental role of ARF in tumor suppression is well-characterized and is principally ascribed to its ability to activate p53 in response to oncogenic signals, such as c-MYC (Lindstrom and Wiman, 2003; Zindy et al., 1998). ARF sequesters MDM2, which is a major ubiquitin E3 ligase of p53, into the nucleolus resulting in stabilization of p53, which instigates cellular senescence (Haupt et al., 1997; Kamijo et al., 1998; Lohrum et al., 2000; Weber et al., 2000b; 1999). Besides the p53-dependent roles, ARF also has p53-independent functions to provoke cellular senescence via interaction with numerous proteins including Tip60, NPM, E2F, and HIF1alpha (Brady et al., 2004; Eymin et al., 2001; Fatyol and Szalay, 2001; Ha et al., 2007; Itahana et al., 2003; Kalinichenko et al., 2004; Leduc et al., 2006; Weber et al., 2000a) (Fig. 1). The tumor suppressive function of ARF is supported by the identification of its genetic and epigenetic alterations in diverse human cancers, such as melanoma, pancreatic adenocarcinoma, glioblastoma, certain leukemia, non-small cell lung cancer, and bladder cancer (Berggren et al., 2003; Chaar et al., 2014; Dominguez et al., 2002; 2003; Esteller et al., 2000; Hsu et al., 2004; Iida et al., 2000; Inda et al., 2006; Ito et al., 2004; Kasahara et al., 2006; Konishi et al., 2002; Lee et al., 2006; Nikolic et al., 2015; Sailasree et al., 2008; Shintani et al., 2001; Silva et al., 2001; 2003; Tannapfel et al., 2002a; 2002b; Zochbauer-Muller et al., 2001). Moreover, p19ARF (the mouse form of ARF) knockout mice are highly tumor-prone, with a high incidence of sarcomas and lymphomas (Eischen et al., 1999; Kamijo et al., 1999). Precise regulation of ARF is important for tumor suppression. Accordingly, studies have addressed its regulation, including transcriptional and relatively less identified post-translational regulation, which has deepened our understanding of the regulatory mechanisms of ARF and their importance for inhibition of tumorigenesis.
In this review, we present the current knowledge concerning the transcriptional and post-translational regulation of ARF, including newly identified regulators controlling ARF protein stability, and the importance of their status as prognostic markers in cancer. And we also suggest the possibility of a therapeutic strategy to restore ARF activities in cancers.
Studies over the past few decades have scrutinized the transcriptional regulation of ARF. Many transcription factors that might regulate ARF expression have been identified, reflecting the functional importance of ARF in tumor suppression. c-MYC is one of the most well-characterized ARF transcription factors (Lindstrom and Wiman, 2003). Upon activation of oncogenic c-MYC, cells execute the OIS fail-safe mechanism to prevent hyper-proliferation through the activation of ARF transcription. c-MYC reportedly binds directly to the E-box element of the
Negative regulators of ARF transcription are as varied as its positive regulators. The polycomb group gene BMI-1 (B cell-specific moloney murine leukemia virus integration site 1) was identified as a transcriptional repressor of ARF (Jacobs et al., 1999a). BMI-1 deficient MEFs manifest premature senescence and impaired proliferation. Both are rescued by the simultaneous deletion of ARF (Jacobs et al., 1999a). Another study demonstrated that BMI-1-containing polycomb-repressive complex 1 (PRC1)-mediated ARF transcription repression requires the EZH2 (the histone methyltransferase enhancer of zeste homolog 2)-containing PRC2 complex to maintain the tri-methylation levels of histone H3 on Lys 27 (H3K27me3) in the
Although many studies of transcriptional regulation of ARF have been done since the 1990s, studies on its post-translational regulation have been conducted only relatively recently. Further research focused on identifying post-translational events that regulate ARF protein stability has defined several regulators of ARF and their importance in tumor suppression.
Although it has been widely assumed that ARF expression is mainly regulated at the transcriptional level, research that focused on the post-translational regulation of ARF revealed that ARF proteins can be ubiquitinated and degraded via proteasomal degradation (Kuo et al., 2004; Sherr, 2006). In 2004, Kuo and colleagues have identified that human ARF, a lysine less protein, and mouse p19ARF, which has a single lysine, can be polyubiquitinated at their N-terminal amino group, followed by proteasomal degradation without any clue to the enzymes mediating this process (Kuo et al., 2004). The first ubiquitin E3-ligase was identified in 2010. The authors observed that TRIP12 induces ARF ubiquitination and proteasomal degradation, which leads to the activation of cellular proliferation. The enzyme was designated ULF (Ubiquitin ligase for ARF). ULF-mediated ARF degradation is negatively regulated by nucleophosmin (NPM) and c-Myc through direct interaction, underscoring the importance of transcription-independent regulation of ARF under oncogenic stress (Chen et al., 2010). Another study described that USP7 accelerates ARF degradation through deubiquitination and stabilization of TRIP12, and promotes the progression of hepatocellular carcinoma (Cai et al., 2015). These findings emphasize the impact of ARF ubiquitination and degradation in cancer development. Subsequently, the second ubiquitin E3-ligase of ARF Makorin 1 (MKRN1) was identified (Ko et al., 2012). Ablation or knock-out of MKRN1 can induce cell growth retardation and cellular senescence through the ubiquitination-dependent degradation of ARF in gastric cancer cell lines, human normal cells, and mouse embryonic fibroblasts (MEFs). MKRN1 ablation can reduce tumor growth of p53 positive and p53 negative gastric cancer cells through the induction of ARF-mediated cellular senescence in a xenograft model. Furthermore, MKRN1 was reported to be highly expressed in well-differentiated gastric carcinoma and was negatively correlation with ARF expression. These results indicate the significance of the post-translational regulation of ARF protein in tumorigenesis. Siva1 was also identified as a ubiquitin E3-ligase of ARF, which inhibits p53 function through ARF polyubiquitination and degradation (Wang et al., 2013). Interestingly, distinct from these mechanisms of ARF degradation mediated by E3 ligases, chaperon HSP90 and ubiquitin E3-ligase, CHIP (Carboxyl terminus of Hsc70-interacting protein) cooperatively induce ubiquitination independent lysosomal degradation of ARF. HSP90 and CHIP form a ternary complex with ARF and accelerate the ubiquitination-independent lysosomal degradation (Han et al., 2017). Ablation or knock-out of CHIP, and ablation or inhibition of HSP90 by its inhibitor, geldanamycin (GA), can induce cell growth retardation and cellular senescence in human normal cells and MEFs. Non-small cell lung cancer (NSCLC) patients with a high expression of HSP90 and CHIP, and low expression of ARF have a significantly worse overall survival rate, and these expression patterns have been implicated as independent prognostic factors. Interestingly, the presence of ARF was reported to significantly increase the sensitivity of NSCLC cancer cells to GA treatment, regardless of endothelial growth factor receptor (EGFR) mutation, ALK (Anaplastic lymphoma kinase) fusion and p53 status, which are frequently identified genetic alterations in NSCLC, suggesting that ARF could be an important criterion for an effective therapeutic strategy using HSP90 inhibitors. HSP90 is recognized as a potent oncogenic protein that stabilizes various growth factor receptors including EGFR and signaling molecules, such as phospho-inoside-3-kinase (PI3K) and AKT, and numerous oncoproteins including mutant p53 (Kamal et al., 2004).
In addition to these functions, these findings suggest a new concept, in which HSP90 can induce the degradation of the ARF tumor suppressor, independent of ubiquitination via chaperone-mediated autophagy (CMA). This event, along with onco-protein stabilization, stimulates tumorigenesis. In addition to these regulatory factors that mediate ARF degradation, a recent paper identified the first deubiquitinase of ARF that induces deubiquitination and stabilization of ARF. Ko and colleagues found that oncogenic c-MYC increases ARF protein stability in addition to its transcription through induction of the deubiquitinase USP10 (Ko et al., 2018). Upon induction by c-Myc, USP10 in turn stimulates deubiquitination followed by stabilization of ARF, which promotes cellular senescence (Ko et al., 2018). Corroborating these findings, the ablation or knockdown of USP10 in human normal cells and MEFs, respectively, induces the bypass of the c-MYC-mediated OIS (Ko et al., 2018). Clinically, the positive correlation of c-MYC expression with USP10 and ARF expression can be disrupted in several cancer cell lines and NSCLC tissues (Ko et al., 2018). These results implicate USP10 could be an important factor that is essential for c-MYC-mediated OIS through the post-translational regulation of ARF (Ko et al., 2018) (Fig. 2).
Further studies revealing the intricate interactions among these regulatory proteins with ARF upon diverse oncogenic stimulation and identifying the correlated signaling pathways disrupted in human cancers will provide more information concerning possible therapeutic targets that could prevent tumorigenesis.
The identification of numerous genetic and epigenetic alterations of the
Tumor suppressive functions of ARF have been demonstrated. ARF is deregulated through gene silencing by promoter hyper-methylation, genetic locus deletion and mutation in numerous human cancers. Research on ARF regulation focused on its transcription have identified numerous positive and negative transcriptional factors of ARF. In addition to transcriptional regulation, post-translational control mechanisms of ARF, which are directly linked to their suppression of tumorigenesis, are being elucidated. Recent research has identified several E3 ubiquitin ligases and deubiquitinase, which control ARF protein stability. The findings suggest the importance of the post-translational regulation of ARF in tumor suppression. They can regulate cellular senescence and tumor growth by controlling the stability of ARF protein in cells and mice xenograft models. Supporting these results, the negative correlation between E3-ubiquitin ligases and ARF protein levels or decreased expression of deubiquitinase and ARF has been detected in several human cancers, and these expression patterns are associated with a significantly low survival rate. Although the post-translational regulators of ARF and their roles in tumorigenesis have been defined, more regulators need to be discovered and how they can be fine-tuned to regulate ARF protein stability upon oncogenic stimuli remains unclear. The presence of various factors affecting ARF stability could be context-dependent and their association with a variety of cancer should be further pursued.
As ARF is one of the well-established tumor suppressors and low levels of ARF protein and mRNA have emerged as an important potential prognostic marker in several human cancers, restoring ARF activity would be a promising therapeutic strategy for cancers. Indeed, given that treatment of GA has a significant cytotoxic effect on ARF-positive NSCLC cell lines compared to ARF-negative cells due to the increased protein stability of ARF, various HSP90 inhibitors including GA analogs developed as cancer drug for clinical trials could be a good therapeutic strategy for NSCLC with high expression of HSP90 and low expression of ARF. Future studies focusing on identifying the complex networks that regulate ARF proteins and their disruption in human cancers will hopefully provide promising therapeutic targets for cancers harboring low expression of ARF proteins.
Transcriptional regulators of ARF.
Transcription factor | Regulation of ARF transcription | Ref. |
---|---|---|
c-Myc | + | 5 |
FoxO | + | 53 |
E2F1 | + | 55 |
E2F3a | + | 56 |
DMP1a | + | 57, 59 |
AML | + | 63 |
p38 | + | 60 |
Smad2/3 | + | 60 |
HKR3 | + | 62 |
BMI-1 | − | 64 |
E2F3b | − | 56 |
DMP1b | − | 59 |
AML/ETO | − | 63 |
CBX7 | − | 66 |
Twist-1 | − | 67 |
TBX2 | − | 68 |
mutant EGFRs | − | 69 |
Positive and negative transcriptional regulators of ARF are indicated in the table. +, up regulation; −, downregulation
Mol. Cells 2018; 41(5): 381-389
Published online May 31, 2018 https://doi.org/10.14348/molcells.2018.0100
Copyright © The Korean Society for Molecular and Cellular Biology.
Aram Ko, Su Yeon Han, and Jaewhan Song*
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
Correspondence to:*Correspondence: jso678@yonsei.ac.kr
ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the
Keywords: ARF, E3 ligases, post-translational modification, transcriptional regulation, tumorigenesis
Uncontrolled cell proliferation is the one of the hallmarks of cancer. Aberrant growth signals or oncogenic stimuli including RAS or c-MYC elicit hyper-proliferation of cells. These processes are normally blocked by a primary fail-safe program including senescence, which is an irreversible cell cycle arrest that restrains aberrant tumor progression (Collado and Serrano, 2010; He and Sharpless, 2017; Lindstrom and Wiman, 2003; Serrano et al., 1997; Zindy et al., 1998). Bypass of the fail-safe program allows cell transformation, with progression of tumorigenesis in normal cells (Brown et al., 1997; Chen et al., 2005; Eischen et al., 1999). The expression of the
The
A fundamental role of ARF in tumor suppression is well-characterized and is principally ascribed to its ability to activate p53 in response to oncogenic signals, such as c-MYC (Lindstrom and Wiman, 2003; Zindy et al., 1998). ARF sequesters MDM2, which is a major ubiquitin E3 ligase of p53, into the nucleolus resulting in stabilization of p53, which instigates cellular senescence (Haupt et al., 1997; Kamijo et al., 1998; Lohrum et al., 2000; Weber et al., 2000b; 1999). Besides the p53-dependent roles, ARF also has p53-independent functions to provoke cellular senescence via interaction with numerous proteins including Tip60, NPM, E2F, and HIF1alpha (Brady et al., 2004; Eymin et al., 2001; Fatyol and Szalay, 2001; Ha et al., 2007; Itahana et al., 2003; Kalinichenko et al., 2004; Leduc et al., 2006; Weber et al., 2000a) (Fig. 1). The tumor suppressive function of ARF is supported by the identification of its genetic and epigenetic alterations in diverse human cancers, such as melanoma, pancreatic adenocarcinoma, glioblastoma, certain leukemia, non-small cell lung cancer, and bladder cancer (Berggren et al., 2003; Chaar et al., 2014; Dominguez et al., 2002; 2003; Esteller et al., 2000; Hsu et al., 2004; Iida et al., 2000; Inda et al., 2006; Ito et al., 2004; Kasahara et al., 2006; Konishi et al., 2002; Lee et al., 2006; Nikolic et al., 2015; Sailasree et al., 2008; Shintani et al., 2001; Silva et al., 2001; 2003; Tannapfel et al., 2002a; 2002b; Zochbauer-Muller et al., 2001). Moreover, p19ARF (the mouse form of ARF) knockout mice are highly tumor-prone, with a high incidence of sarcomas and lymphomas (Eischen et al., 1999; Kamijo et al., 1999). Precise regulation of ARF is important for tumor suppression. Accordingly, studies have addressed its regulation, including transcriptional and relatively less identified post-translational regulation, which has deepened our understanding of the regulatory mechanisms of ARF and their importance for inhibition of tumorigenesis.
In this review, we present the current knowledge concerning the transcriptional and post-translational regulation of ARF, including newly identified regulators controlling ARF protein stability, and the importance of their status as prognostic markers in cancer. And we also suggest the possibility of a therapeutic strategy to restore ARF activities in cancers.
Studies over the past few decades have scrutinized the transcriptional regulation of ARF. Many transcription factors that might regulate ARF expression have been identified, reflecting the functional importance of ARF in tumor suppression. c-MYC is one of the most well-characterized ARF transcription factors (Lindstrom and Wiman, 2003). Upon activation of oncogenic c-MYC, cells execute the OIS fail-safe mechanism to prevent hyper-proliferation through the activation of ARF transcription. c-MYC reportedly binds directly to the E-box element of the
Negative regulators of ARF transcription are as varied as its positive regulators. The polycomb group gene BMI-1 (B cell-specific moloney murine leukemia virus integration site 1) was identified as a transcriptional repressor of ARF (Jacobs et al., 1999a). BMI-1 deficient MEFs manifest premature senescence and impaired proliferation. Both are rescued by the simultaneous deletion of ARF (Jacobs et al., 1999a). Another study demonstrated that BMI-1-containing polycomb-repressive complex 1 (PRC1)-mediated ARF transcription repression requires the EZH2 (the histone methyltransferase enhancer of zeste homolog 2)-containing PRC2 complex to maintain the tri-methylation levels of histone H3 on Lys 27 (H3K27me3) in the
Although many studies of transcriptional regulation of ARF have been done since the 1990s, studies on its post-translational regulation have been conducted only relatively recently. Further research focused on identifying post-translational events that regulate ARF protein stability has defined several regulators of ARF and their importance in tumor suppression.
Although it has been widely assumed that ARF expression is mainly regulated at the transcriptional level, research that focused on the post-translational regulation of ARF revealed that ARF proteins can be ubiquitinated and degraded via proteasomal degradation (Kuo et al., 2004; Sherr, 2006). In 2004, Kuo and colleagues have identified that human ARF, a lysine less protein, and mouse p19ARF, which has a single lysine, can be polyubiquitinated at their N-terminal amino group, followed by proteasomal degradation without any clue to the enzymes mediating this process (Kuo et al., 2004). The first ubiquitin E3-ligase was identified in 2010. The authors observed that TRIP12 induces ARF ubiquitination and proteasomal degradation, which leads to the activation of cellular proliferation. The enzyme was designated ULF (Ubiquitin ligase for ARF). ULF-mediated ARF degradation is negatively regulated by nucleophosmin (NPM) and c-Myc through direct interaction, underscoring the importance of transcription-independent regulation of ARF under oncogenic stress (Chen et al., 2010). Another study described that USP7 accelerates ARF degradation through deubiquitination and stabilization of TRIP12, and promotes the progression of hepatocellular carcinoma (Cai et al., 2015). These findings emphasize the impact of ARF ubiquitination and degradation in cancer development. Subsequently, the second ubiquitin E3-ligase of ARF Makorin 1 (MKRN1) was identified (Ko et al., 2012). Ablation or knock-out of MKRN1 can induce cell growth retardation and cellular senescence through the ubiquitination-dependent degradation of ARF in gastric cancer cell lines, human normal cells, and mouse embryonic fibroblasts (MEFs). MKRN1 ablation can reduce tumor growth of p53 positive and p53 negative gastric cancer cells through the induction of ARF-mediated cellular senescence in a xenograft model. Furthermore, MKRN1 was reported to be highly expressed in well-differentiated gastric carcinoma and was negatively correlation with ARF expression. These results indicate the significance of the post-translational regulation of ARF protein in tumorigenesis. Siva1 was also identified as a ubiquitin E3-ligase of ARF, which inhibits p53 function through ARF polyubiquitination and degradation (Wang et al., 2013). Interestingly, distinct from these mechanisms of ARF degradation mediated by E3 ligases, chaperon HSP90 and ubiquitin E3-ligase, CHIP (Carboxyl terminus of Hsc70-interacting protein) cooperatively induce ubiquitination independent lysosomal degradation of ARF. HSP90 and CHIP form a ternary complex with ARF and accelerate the ubiquitination-independent lysosomal degradation (Han et al., 2017). Ablation or knock-out of CHIP, and ablation or inhibition of HSP90 by its inhibitor, geldanamycin (GA), can induce cell growth retardation and cellular senescence in human normal cells and MEFs. Non-small cell lung cancer (NSCLC) patients with a high expression of HSP90 and CHIP, and low expression of ARF have a significantly worse overall survival rate, and these expression patterns have been implicated as independent prognostic factors. Interestingly, the presence of ARF was reported to significantly increase the sensitivity of NSCLC cancer cells to GA treatment, regardless of endothelial growth factor receptor (EGFR) mutation, ALK (Anaplastic lymphoma kinase) fusion and p53 status, which are frequently identified genetic alterations in NSCLC, suggesting that ARF could be an important criterion for an effective therapeutic strategy using HSP90 inhibitors. HSP90 is recognized as a potent oncogenic protein that stabilizes various growth factor receptors including EGFR and signaling molecules, such as phospho-inoside-3-kinase (PI3K) and AKT, and numerous oncoproteins including mutant p53 (Kamal et al., 2004).
In addition to these functions, these findings suggest a new concept, in which HSP90 can induce the degradation of the ARF tumor suppressor, independent of ubiquitination via chaperone-mediated autophagy (CMA). This event, along with onco-protein stabilization, stimulates tumorigenesis. In addition to these regulatory factors that mediate ARF degradation, a recent paper identified the first deubiquitinase of ARF that induces deubiquitination and stabilization of ARF. Ko and colleagues found that oncogenic c-MYC increases ARF protein stability in addition to its transcription through induction of the deubiquitinase USP10 (Ko et al., 2018). Upon induction by c-Myc, USP10 in turn stimulates deubiquitination followed by stabilization of ARF, which promotes cellular senescence (Ko et al., 2018). Corroborating these findings, the ablation or knockdown of USP10 in human normal cells and MEFs, respectively, induces the bypass of the c-MYC-mediated OIS (Ko et al., 2018). Clinically, the positive correlation of c-MYC expression with USP10 and ARF expression can be disrupted in several cancer cell lines and NSCLC tissues (Ko et al., 2018). These results implicate USP10 could be an important factor that is essential for c-MYC-mediated OIS through the post-translational regulation of ARF (Ko et al., 2018) (Fig. 2).
Further studies revealing the intricate interactions among these regulatory proteins with ARF upon diverse oncogenic stimulation and identifying the correlated signaling pathways disrupted in human cancers will provide more information concerning possible therapeutic targets that could prevent tumorigenesis.
The identification of numerous genetic and epigenetic alterations of the
Tumor suppressive functions of ARF have been demonstrated. ARF is deregulated through gene silencing by promoter hyper-methylation, genetic locus deletion and mutation in numerous human cancers. Research on ARF regulation focused on its transcription have identified numerous positive and negative transcriptional factors of ARF. In addition to transcriptional regulation, post-translational control mechanisms of ARF, which are directly linked to their suppression of tumorigenesis, are being elucidated. Recent research has identified several E3 ubiquitin ligases and deubiquitinase, which control ARF protein stability. The findings suggest the importance of the post-translational regulation of ARF in tumor suppression. They can regulate cellular senescence and tumor growth by controlling the stability of ARF protein in cells and mice xenograft models. Supporting these results, the negative correlation between E3-ubiquitin ligases and ARF protein levels or decreased expression of deubiquitinase and ARF has been detected in several human cancers, and these expression patterns are associated with a significantly low survival rate. Although the post-translational regulators of ARF and their roles in tumorigenesis have been defined, more regulators need to be discovered and how they can be fine-tuned to regulate ARF protein stability upon oncogenic stimuli remains unclear. The presence of various factors affecting ARF stability could be context-dependent and their association with a variety of cancer should be further pursued.
As ARF is one of the well-established tumor suppressors and low levels of ARF protein and mRNA have emerged as an important potential prognostic marker in several human cancers, restoring ARF activity would be a promising therapeutic strategy for cancers. Indeed, given that treatment of GA has a significant cytotoxic effect on ARF-positive NSCLC cell lines compared to ARF-negative cells due to the increased protein stability of ARF, various HSP90 inhibitors including GA analogs developed as cancer drug for clinical trials could be a good therapeutic strategy for NSCLC with high expression of HSP90 and low expression of ARF. Future studies focusing on identifying the complex networks that regulate ARF proteins and their disruption in human cancers will hopefully provide promising therapeutic targets for cancers harboring low expression of ARF proteins.
. Transcriptional regulators of ARF..
Transcription factor | Regulation of ARF transcription | Ref. |
---|---|---|
c-Myc | + | 5 |
FoxO | + | 53 |
E2F1 | + | 55 |
E2F3a | + | 56 |
DMP1a | + | 57, 59 |
AML | + | 63 |
p38 | + | 60 |
Smad2/3 | + | 60 |
HKR3 | + | 62 |
BMI-1 | − | 64 |
E2F3b | − | 56 |
DMP1b | − | 59 |
AML/ETO | − | 63 |
CBX7 | − | 66 |
Twist-1 | − | 67 |
TBX2 | − | 68 |
mutant EGFRs | − | 69 |
Positive and negative transcriptional regulators of ARF are indicated in the table. +, up regulation; −, downregulation.
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