Elevated expression of iASPP in head and neck squamous cell carcinoma and its clinical significance

Liu, Zhengzheng; Zhang, Xin; Huang, Donghai; Liu, Yong; Zhang, Xiaozhe; Liu, Lijun; Li, Guo; Dai, Yaozhang; Tan, Haolei; Jian-yun, Xiao; Tian, Yongquan

doi:10.1007/s12032-012-0306-9

Cited by 25 publications

(24 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The apoptotic function of p53 is potentiated by ASPP1 and ASPP2, whereas a third family member, iASPP, negatively modulates it. iASPP (encoded by PPP1R13L) is evolutionarily conserved from worm to human, and its expression is frequently upregulated in human cancers (Bergamaschi et al, 2003;Bergamaschi et al, 2006;Cao et al, 2013;Chen et al, 2010;Kabeya et al, 2000;Liu et al, 2009;Liu et al, 2012;Lu et al, 2010;Mantovani et al, 2007;Saebø et al, 2006;Zhang et al, 2005). iASPP is expressed predominantly in epithelial cells, in the skin, testis, heart and stomach (Herron et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

BSTRACTThe protein iASPP (encoded by PPP1R13L) is an evolutionarily conserved p53 inhibitor, the expression of which is often upregulated in human cancers. We have recently shown that iASPP is a crucial regulator of epidermal homeostasis. Here, we report that iASPP also acts as autophagy inhibitor in keratinocytes. Our data show that depletion of iASPP protects keratinocytes from apoptosis by modulating the expression of Noxa (also known as PMAIP1). In our model, iASPP expression can affect the fissionfusion cycle, mass and shape of mitochondria. iASPP-silenced keratinocytes display disorganization of cytosolic compartments and increased metabolic stress caused by deregulation of mTORC1 signaling. Moreover, increased levels of lipidated LC3 protein confirmed the activation of autophagy in iASPP-depleted cells. We have identified a novel mechanism modulating autophagy in keratinocytes that relies upon iASPP expression specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction that is essential for autophagosome formation or maturation. Using organotypic culture, we further explored the link between autophagy and differentiation, and we showed that impairing autophagy affects epidermal terminal differentiation. Our data provide an alternative mechanism to explain how epithelial integrity is maintained against environmental stressors and might also improve the understanding of the etiology of skin diseases that are characterized by defects in differentiation and DNA damage responses.

show abstract

Section: Introductionmentioning

confidence: 99%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Expression was abundant in the tumor-derived cell lines and lower in the lymphoblastoid cell line (LCL) that was established by in vitro infection with Epstein-Barr virus (EBV). This is consistent with reports of upregulated expression of iASPP being associated with malignant transformation (75,76).…”

Section: Establishment Of the Screening Assaysupporting

confidence: 93%

A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP

Woodard

Liao

Goodwin

et al. 2015

J Virol

View full text Add to dashboard Cite

The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein is essential for the replication and maintenance of virus genomes in latently KSHV-infected cells. LANA also drives dysregulated cell growth through a multiplicity of mechanisms that include altering the activity of the cellular kinases extracellular signal-regulated kinase (ERK) and glycogen synthase kinase 3 (GSK-3). To investigate the potential impact of these changes in enzyme activity, we used protein microarrays to identify cell proteins that were phosphorylated by the combination of ERK and GSK-3. The assays identified 58 potential ERK-primed GSK-3 substrates, of which 23 had evidence for in vivo phosphorylation in mass spectrometry databases. Two of these, SMAD4 and iASPP, were selected for further analysis and were confirmed as ERK-primed GSK-3 substrates. Cotransfection experiments revealed that iASPP, but not SMAD4, was targeted for degradation in the presence of GSK-3. iASPP interferes with apoptosis induced by p53 family members. To determine the importance of iASPP to KSHV-infected-cell growth, primary effusion lymphoma (PEL) cells were treated with an iASPP inhibitor in the presence or absence of the MDM2 inhibitor Nutlin-3. Drug inhibition of iASPP activity induced apoptosis in BC3 and BCBL1 PEL cells but did not induce poly(ADP-ribose) polymerase (PARP) cleavage in virus-negative BJAB cells. The effect of iASPP inhibition was additive with that of Nutlin-3. Interfering with iASPP function is therefore another mechanism that can sensitize KSHV-positive PEL cells to cell death. IMPORTANCEKSHV is associated with several malignancies, including primary effusion lymphoma (PEL). The KSHV-encoded LANA protein is multifunctional and promotes both cell growth and resistance to cell death. LANA is known to activate ERK and limit the activity of another kinase, GSK-3. To discover ways in which LANA manipulation of these two kinases might impact PEL cell survival, we screened a human protein microarray for ERK-primed GSK-3 substrates. One of the proteins identified, iASPP, showed reduced levels in the presence of GSK-3. Further, blocking iASPP activity increased cell death, particularly in p53 wild-type BC3 PEL cells.T he Kaposi's sarcoma-associated herpesvirus (KSHV) latencyassociated nuclear antigen (LANA) is expressed in all KSHVinfected cells, including the tumor cells of the KSHV-associated malignancies Kaposi's sarcoma, primary effusion lymphoma (PEL), and muticentric Castleman disease. LANA functions in the replication and maintenance of latent, episomal KSHV genomes (1, 2) by binding to the KSHV origin of replication in the terminal repeats (3, 4), recruiting cellular replication proteins (5-11), and tethering the KSHV episomal genomes to host chromosomes (12-18). Sequences in the KSHV terminal repeats are bound by the C terminus of LANA, and the X-ray crystal structures of the human and murine gammaherpesvirus 68 (MHV68) LANA DNA-binding domains have been solved (19)(20)(21).KSHV infection leads to a global reprogramming of cel...

show abstract

“…In addition, it is also reported that PPP1R3L is also involved in tumorigenesis, cell growth, cell cycle progression, metastasis and chemoresistance (24)(25)(26)(27). In glioblastoma cells, silencing of PPP1R3L leads to cell proliferation inhibition and cell cycle arrest (28).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L

Zhao

Yang-de

2013

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Abstract. plays an important role in regulating growth, invasiveness, stem-like traits, differentiation and apoptosis of glioblastoma cells. PPP1R3L, an inhibitory member of the apoptosis-stimulating protein of p53 family (IASPP), is also able to affect growth, cell cycle progression, metastasis and apoptosis of various types of cancer. To investigate the regulation of PPP1R13L expression by miR-124 and their effects on proliferation, cell cycle transition and invasion in glioblastoma cells, U251 and U373 glioblastoma cells were transfected with miR-124 mimics, its negative control (NC) or an inhibitor. We found that miR-124 was downregulated in glioblastoma tissues, and inversely regulated PPP1R13L expression in U251 and U373 glioblastoma cells. PPP1R13L was found to be a direct target of miR-124 in glioblastoma cells. Overexpression of miR-124 inhibited proliferation, G1/S transition and invasiveness in glioblastoma cells. miR-124 downregulation-mediated malignant progression of glioblastoma was partly attributed to increased PPP1R13L expression. Consequently, our findings provide a molecular basis for the role of miR-124/PPP1R13L in the progression of human glioblastoma and suggest a novel target for the treatment of glioblastoma.

show abstract

Elevated expression of iASPP in head and neck squamous cell carcinoma and its clinical significance

Cited by 25 publications

References 30 publications

iASPP is a novel autophagy inhibitor in keratinocytes

iASPP is a novel autophagy inhibitor in keratinocytes

A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP

Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L

Contact Info

Product

Resources

About