1 Tumour Protein 53-Induced Nuclear Protein 1 (TP53INP1) Enhances

Home , Gene nomenclature, P53AIP1, TP53INP1

Tumour protein 53-induced nuclear protein 1 (TP53INP1) enhances p53

function and represses tumourigenesis

Jeyran Shahbazi1,2, Richard Lock1 and Tao Liu1,3*

1Children’s Cancer Institute Australia for Medical Research, Randwick, Sydney,

NSW 2031, Australia

2School of Biotechnology and Biomolecular Sciences, University of New South

Wales, Kensington, Sydney, NSW 2052, Australia

3School of Women's & Children's Health, UNSW Medicine, University of New South

Wales, Randwick, Sydney, NSW 2031, Australia

Running title: TP53INP1 represses tumourigenesis

*Correspondence: Tao Liu, Children’s Cancer Institute Australia, Lowy Cancer

Research Centre, University of New South Wales, Kensington, Sydney, NSW 2052,

Australia. E-mail: [email protected]

Abstract

The tumor protein 53-induced nuclear protein 1 (TP53INP1) gene is a stress-induced p53 target gene whose expression is modulated by transcription factors such as p53, p73 and E2F1. TP53INP1 gene encodes two isoforms of TP53INP1 proteins, TP53INP1α and TP53INP1β, both of which appear to be key elements in p53 function. When associated with homeodomain-interacting protein kinase-2 (HIPK2), TP53INP1 phosphorylates p53 protein at Serine 46, enhances p53 protein stability and its transcriptional activity, leading to transcriptional activation of p53 target genes such as p21, PIG-3 and MDM2, cell growth arrest and apoptosis upon DNA damage stress. The anti-proliferative and pro-apoptotic activities of TP53INP1 indicate that TP53INP1 has an important role in cellular homeostasis and DNA damage response. Deficiency in TP53INP1 expression results in increased tumourigenesis; while TP53INP1 expression is repressed during early stages of cancer by factors such as miR-155. This review aims to summarize the roles of TP53INP1 in blocking tumor progression through p53-dependant and p53- independent pathways, as well as the elements which repress TP53INP1 expression, hence highlighting its potential as a therapeutic target in cancer treatment.

INTRODUCTION

The tumor protein 53-induced nuclear protein 1 (TP53INP1) is expressed in many tissues upon exposure to various stress agents, and encodes two nuclear isoforms,

TP53INP1α and TP53INP1β, both of which appear to be key elements in p53- mediated cell cycle arrest and apoptosis in different cell types upon cellular stress.

TP53INP1 gene localizes to human chromosome 8q22 (Nowak et al., 2005), which shows conserved synergy with the A1-A2 of the murine chromosome 4 where the mouse TP53INP1 was mapped (Carrier et al., 2000). Sequence analysis by the

HUGO Gene Nomenclature Committee has revealed that stress induced protein (SIP), p53-dependent damage-inducible nuclear protein 1 (p53DINP1) and thymus- expressed acidic protein (TEAP) are in fact TP53INP1.

Originally named SIP, TP53INP1 was first cloned and characterized by

Tomasini et al in an attempt to identify pancreatic genes induced by the cellular stress acute pancreatitis in the mouse, using a quantitative fluorescent cDNA microarray hybridization approach (Tomasini, 2001). The mouse SIP gene is almost 20 kilobase pairs in length with five exons. The exon four of 28 base pairs is alternatively spliced to generate two transcripts which translates into two nuclear proteins of 18 and 27 kDa, SIP18 and SIP27 (Tomasini, 2001) corresponding to TP53INP1 and TP53INP1 respectively (Tomasini, 2003). TP53INP1 and TP53INP1 proteins differ in their C- terminal region and can promote cell death by apoptosis when over-expressed

(Tomasini, 2001). Both TP53INP1 and TP53INP1 are rapidly and strongly induced in pancreatic acinar cells during the acute phase of pancreatitis and the exposure to various stress agents such as UV, base damaging, ethanol, heat shock and oxidative stress.

TP53INP1 (SIP27) is also identical to thymus-expressed acidic (TEAP) (Carrier et al., 1999). TEAP protein is mainly localized in the nucleus as shown by EGFP- tagged TEAP fusion protein. Importantly, TEAP mRNA is activated in response to cellular stresses, and TEAP protein over expression induces cell death (Tomasini et al., 2002).

1. Modulation of TP53INP1 gene expression

Modulation of TP53INP1 gene expression by p53

Multiple lines of evidence suggest that TP53INP1 gene expression is modulated by p53. While TP53INP1 gene transcription is induced by cellular stress, cells with deleted, mutated or inactive p53 are unable to activate TP53INP1 gene expression in response to stress agents, suggesting that regulation of TP53INP1 gene expression is dependent on p53 (Tomasini et al., 2002). Consistently, there exists a functional p53- response element within the promoter region of the TP53INP1 gene, and mouse embryo fibroblasts transformed with rasV12/E1A to activate p53 dependent pathway, compared to fibroblasts without p53 activity, show stronger induction of TP53INP1 mRNA expression (Tomasini et al., 2002). These observations suggest that TP53INP1 gene expression is activated by p53 in response to stress or transformation in cells expressing wild-type p53.

p53DINP1, a p53 inducible gene, regulates p53-dependant apoptosis

Apoptosis is one of the most important tumour suppressive functions of p53. The challenge to find the exact mechanisms of p53-dependent apoptosis remains ongoing.

In 2000, it was shown by Oda et al that phosphorylation of p53 at Ser-46 by p53 target genes such as p53 regulated apoptosis inducing protein 1 (p53AIP1), could specifically regulate the induction of apoptosis (Oda et al., 2000). p53AIP1 was isolated as novel p53 target gene in an attempt by Oda et al who used yeast enhancer trap system that allowed direct cloning of p53 binding sequence from human genomic

DNA in order to isolate p53 target genes. p53AIP1 gene expression was strongly inducible by DNA damage in a p53 dependent manner. Importantly, phosphorylation of p53 at Ser-46 regulated the induction of P53AIP1 specifically because p53AIP1 induction was greatly impaired in p53 Ser-46 mutant tumours (Oda et al., 2000), and p53 phosphorylation at Ser-46 induced apoptosis.

In quest to find how p53 was phosphorylated at Ser-46, Okamura et al from the same group used a differential display method combined with a cell line that carried a well-controlled expression system for wild-type p53 to isolate TP53INP1, which was involved in the regulation of p53 phosphorylation at Ser-46 and the induction of p53AIP1 (Okamura et al., 2001). Importantly, TP53INP1 induced p53 phosphorylation at Ser-46 and p53AIP1 expression whereas the inhibition of

TP53INP1 expression clearly impaired p53 phosphorylation at Ser-46 and p53AIP1 expression. Therefore, TP53INP1 is required for p53 phosphorylation at Ser-46 and the induction of apoptosis associated genes like p53AIP1(Okamura et al., 2001).

The mechanism underlying TP53INP1 gene expression modulation by p53

As mentioned earlier, Okamura quite clearly illustrated that p53DINP1 which is

TP53INP1 forms a complex with a kinase to phosphorylate p53 at Ser46; however the kinase remained unknown in his work. On the other hand, two separate studies demonstrated that homeodomain-interacting protein kinase-2 (HIPK2), a member of a

5 novel family of nuclear serine/threonine kinases interacts and activates p53 by directly phosphorylating it at Ser46. HIPK2 localizes with p53 and PML-3 into the nuclear bodies and is activated after irradiation with ultraviolet, activating the p53 dependent transcription and apoptotic pathway (Hofmann et al., 2002; D'Orazi et al.,

2001).

Following all these, Tomasini and his group investigated the interactions between

TP53INP1 and HIPK2 in regulating p53 apoptotic pathway. Their results showed that

TP53INP1 physically interacts with HIKP2 and p53. Further analysis of subcellular distributions showed that p53, HIPK2, and both TP53INP1 and TP53INP1 are localized into pro-myelocytic leukemia nuclear bodies, PML-NB, which are cell cycle- regulated nuclear structures that appear as punctate foci in interphase nuclei .

Such co-localization facilitates the interactions by positioning the resulting complex near its site of action (Tomasini, 2003).

They had also studied the functional relationship between TP53INP1 and p53 and surprising they found that both isoforms of TP53INP1 in association with HIPK2 regulates p53 transcriptional activity on p21, mdm2, pig3, and bax promoters. Flow cytometry analysis revealed that TP53INP1s overexpression induces G1 arrest and increases p53-mediated apoptosis (Tomasini, 2003).

In another study by Yoshida, it was demonstrated that another protein kinase C 

(PCK) also associates with p53, mediating its phosphorylation on Ser46 upon exposure to genotoxic agents. Hence promoting p53-mediated apoptosis in cellular response to DNA damage. Their further investigations demonstrated an inducible

6 binding of PCK with TP53INP1 following genotoxic stress (Yoshida et al., 2006).

Therefore, the possibility exists that PCK could be another kinase that interacts physically with TP53INP1 formingg a complex to regulate p53-induced apoptosis though phosphorylating it on Ser46.

In conclusion, upon initial DNA damage, p53 is phosphorylated at Ser-15 and Ser-20, stimulating the binding of p53 to promoter region of a subset of genes such as G1 arrest genes (p21), DNA repair genes (p53R2) and p53 negative regulators such as mDDM2. On the other hand, If DNA damage is sever, p53DINP1 is likely to form a complex with an unidentified Ser46 kinase to phosphorylate p53 at Ser46, promoting the binding of p53 to apoptosis relatted genes such as p53AIP1 ratherr than the repair related genes (Oda et al., 2000) and (Okamura et al., 2001) as illustrateed in figure 1.

Figure1: DNA damage response and p53 pathway activation. Upon initial DNA damage, p53 is phosphorylated at Ser-15 and Ser-20, stimulating the binding of p53 to promoter region of a subset of genes such as G1 arrest genes (p21), DNA repair genes (p53R2) and p53 negative regulators. On the other hand, If DNA damage is sever, p53DINP1 is likely to form a complex with an two Ser46 kinase such as HIPK2 and PKCδ to phosphorylate p53 at Ser46, promoting the binding of p53 to apoptosis related genes such as p53AIP1 rather than the repair related genes.

Transcriptional induction of TP53INP1 by p73 in p53-independent manner

Transcription of TP53INP1 was also strongly induced in the absence of p53, in the pancreas of p53-null mice with acute pancreatitis upon exposure to cisplatin. Further studies by Tomasini using p53 deficient cells demonstrated a direct functional association between TP53INP1 and p73, a p53 homologue, to regulate cell cycle progression and apoptosis independently from p53. Overexpression of p73 can activate the expression of p53 target genes and induce cell cycle arrest and/or apoptosis (Kaghad et al., 1997; Jost et al., 1997). Several independent studies have shown that p73 can bind p53-responsive elements activating p53 target genes (Obad et al., 2004). It is known that p73 is stabilized only in response to cisplatin, - irradiation and oncogenes (E1A and HPVE6) (Hamer et al., 2001; Shimodaira et al.,

2003). Cisplatin is a strong DNA damaging agent able to induce cell cycle arrest and apoptosis in a p53-independent manner through activation of p73 pathway (De

Laurenzi et al., 2000).

P73 activity of TP53INP1 promoter requires the presence of p53 responsive element that is located between 1364 and 1239 base pairs as previously demonstrated by

Tomasini (2002). This suggested that p73 over expression can mediate direct transcriptional regulation of TP53INP1, inducing apoptosis. Although worth mentioning that TP53INP1 is able to stimulate p53 activity at much higher level compared to p73 activity. The most important conclusion is that in the absence of functional p53, TP53INP1 can activate p73 to induce cell death; hence the activation of TP53INP1 could potentially prevent tumor development.

TP53INP1, proapoptotic cofactors of p53 is transcriptionally upregulated by

E2F transcription factor

E2F1 is a transcription factor inducing apoptosis via both p53 dependent and

independent manner. A recent study by Hershko (Hershko et al., 2005) showed that

excessive activity of E2F1 results in increased expression of TP53INP1 as well as

several other cofactors of p53 such as ASPP1, ASPP2 and JMY through a direct

transcriptional mechanism. Similarly to TP53INP1, E2F1 induced phosphorylation of

p53 at serine 46 was also detected. There remains an important question whether

E2F1 can also regulate the expression of HIPK2, the kinase that mediates p53

phosphorylation at Ser 46. Upon p53 phosphorylation at Ser 46, another proapoptotic

gene, P53AIP1, is transcriptionally activated (Oda et al., 2000) which its expression

was increased upon E2F1 activation in p53 deficient cells, suggesting that p53AIP1

might be regulated by E2F1 independently to p53 (Hershko et al., 2005). Taking all

these data together, we could perhaps hypothesis that in the absence of p53, E2F1

could be modulating P53AIP1 expression and inducing apoptosis via a totally

difference mechanism.

Micro-RNA act as tumor suppressor by targeting TP53INP1

MicroRNAs (miRNAs) are a new class of small (21-23 nucleotide) noncoding RNAs

that function as post-transcriptional regulators of gene expression through base-

pairing to complementary sites on their target mRNAs and are involved in

carcinogenesis. Many articles have reported that TP53INP1 could be regulated by

miRNAs at the post-transcriptional level.

For instance, TP53INP1 is a direct target of miR-130b which promotes CD133(+) liver tumor-initiating cell growth (Ma et al., 2010). Two up-regulated miRNAs in

HTLV-1– transformed human T-cell lines target the 3’ untranslated region (3’UTR)

of the mRNA for a tumor suppressor protein, tumor protein 53–induced nuclear

protein 1. While knocking down these two miRNAs significantly increases TP53INP1

expression, reducing the proliferation and survival of HTLV-1 infected/transformed

cells (Yeung et al., 2008). Also TP53INP1 expression is down-regulated by a

genomic micro RNA miR-155 which is overexpressed in pancreatic cancer cells,

interacting with TP53INP1 mRNA 3`UTR (Gironella et al., 2007).

In a separate study, TP53INP1 was also found to be the direct downstream target of another microRNA, miR-125b, which was overexpressed in type II endometrial carcinoma cells compared with type I, contributing to malignancy of type II EC possibly through down-regulating TP53INP1 (Jiang et al., 2011). Various studies have established miR-125b as an oncogene in several difference types of human tumors. Such regulatory function among TP53INP1 and miR-125b could potentially provide significant input for more effective therapy.

Another study demonstrated TP53INP1 to be a target gene for another micro-RNA, miR-17-5p. miR-17-5p suppressed cell growth and promoted apoptosis of cervical cancer cells, whereas the effects of TP53INP1 were opposite, and ectopic expression of TP53INP1 counteracted the suppression of cell growth caused by miR-17-5p. The same correlations between miR-17-5p and TP53INP1 were observed in cervical cancer tissues. Together, these results indicated that miR-17-5p functions as a tumor suppressor in cervical cancer cells by targeting TP53INP or perhaps TP53INP1 functions as a oncogene in cervical cancer (Wei et al., 2012). On the other hand, studies in Chronic lymphocytic leukemia (CLL) showed that miR-17 ~ 92 family

reduced the expression of tumor suppressor genes such as TP53INP1, E2F5, TRIM8

and ZBTB4 whereby protecting cells from apoptosis(Bomben et al., 2012).

2. Functions of TP53INP1

TP53INP1 interacts with a family of proteins involved in autophagy. TP53INP1, mainly a nuclear protein, relocalizes in autophagosomes during autophagy where it is eventually degraded and it interacts with ATG8-family proteins to induce autophagy- dependent cell death. Under normal conditions, TP53INP1 is absent where p62 binds ubiquitinated proteins and LC3-II on the membrane of the autophagosomes which is considered a prop-survival mechanism. However; upon cellular stress,53 activates

TP53INP1 transcription. TP53INP1 interacts with LC3 via a functional LC3-

interacting region (LIR) motif with much higher affinity compared to p62, resulting in

a partial displacement of p62 which ultimately results in TP53INP1 promoted

autophagy dependent cell death (Seillier et al., 2012).

Another study was published soon after Seillier showing that human TP53INP1

regulates autophagy. Their sequence studies identified a functional and conserved

LC3-interacting motif (LIR) in region 1 of TP53INP1 proteins. They confirmed that

TP53INP1 and DOR/TP53INP2 act as dual regulators of transcription and autophagy

(Sancho et al., 2012).

A later study by Seux (Seux et al., 2011) observed that TP53INP1 inactivation is

correlated with increased cell migration in mouse embryonic fibroblast and different

pancreatic cancer cell lines. TP53INP1 expression reversely affects secreted protein

acidic and rich in cysteine (SPARC) expression. SPARC regulates cell-matrix

interactions and has been shown to be up-regulated in normal pancreas as well as in

pancreatic tissue only when TP53INP1 is not present. This novel finding could further

explain TP53INP1 tumor suppressor function by modulating cellular migration during metastasis.

3. TP53INP1 in disease other than cancer

Tumour protein 53-induced nuclear protein 1 (TP53INP1) is a p53 induced cell stress response protein. Over expression of TP53INP1 induces cell cycle arrest in G1 phase and enhances p53-mediated apoptosis. Various studies have previously validated the relationship between inflammatory cytokines and increased risk of developing prostate cancer. A recent study investigated whether inflammatory cytokines could induce TP53INP1 expression. And interestingly, they found that stimulation of

LNCaP cells with inflammatory cytokines (TNFalpha and IL6) enhances the expression of TP53INP1 mRNA, suggesting that TP53INP1 over-expression could be involved in inflammation mediated prostatic carcinogenesis (Giusiano et al., 2012).

4. Therapeutic approach: Restoring Tumor protein 53-induced nuclear protein 1

expression could possibly inhibit tumor development

Expression of TP53INP1 was analyzed by immunohistochemistry in healthy and diseased pancreas tissues, demonstrating that TP53INP1 is present in nonmalignant human pancreatic lesions, whereas it is significantly or completely lost in the majority of primary PDAC and is absent in metastasis. In an attempt to restore TP53INP1 expression in tumor, pancreatic cancer development was inhibited; such results indicates that TP53INP1 might be an indicator of pancreatic malignancy (Gironella et al., 2007). One of their interesting observation was the TP53INP1 mRNA level

remained unchanged among tumor and adjacent normal tissues whereas the protein

expression was significantly reduced in PDAC, pointing out a translational or

posttranslational regulations of TP53INP1 expression,

Significant reduction of TP53INP1 was also detected in human gastric cancer (Jiang

et al., 2006), colon (refrence), pancreatic and intestinal endocrine tumors(refrence) (

perhaps add afew more examples of tumors where tp53inp1 is reduced: expression is

also lost in other cancers as: rat pre- neoplastic lesions in liver (Suzuki et al., 2004;

Ogawa et al., 2005) and during breast or gastric cancer progression in human (Ito et al., 2006; Jiang et al., 2006). These investigations all demonstrate the lack of

TP53INP1 expression might be a general feature of tumor development, and its restoration could perhaps prevent further tumor development.

Conclusion

Tumor suppressive function of p53 reflects physiological activities of wide range of target genes, therefore identification of additional p53 target gene could expand our knowledge regarding pathways involved in tumorigenesesis and mechanisms through which cells are protected from cellular stress.

TP53INP1 (tumor protein 53-induced nuclear protein 1) is a stress-induced p53 target gene. TP53INP1 expression is lost at easy stage of tumor progression and various researches has shown that its restoration could potentially inhibit tumor growth via its

antiproliferative and proapoptotic activities.

Tp53INP1 is able to interact physically with homeodomain-interacting protein kinase-

2 (HIPK2) and protein kinase Cδ upon exposure to genotoxic agents, modulating p53 transcriptional activity through phosphorylation at Ser-46. Finally, the E2F1 transcription factor, also a major effector of cell proliferation and apoptosis, is involved in TP53INP1 transcriptional regulation

The TP53INP1 gene encodes two protein isoforms, TP53INP1α and TP53INP1β.

Overexpression of both isoforms induces cell cycle arrest and apoptosis in several cell lines, even in the absence of p53. In this case, TP53INP1 is functionally associated with p73, regulating cell cycle progression and apoptosis, independently from p53. In addition, TP53INP1 interacts with LC3 and ATG8-family proteins and induces autophagy-dependent cell death and it is also involved in cellular migration via regulating SPARC expression.

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