Expression of the RAI gene is conducive to apoptosis: Studies of induction and interference

Laska, Magdalena Janina; Strandbygård, Dorthe; Kjeldgaard, Anette Hvenegaard; Mains, Mette; Corydon, Thomas J.; Memon, Ashfaque A.; Sørensen, Boe Sandahl; Vogel, Ulla; Jensen, Uffe Birk; Nexø, Bjørn A.

doi:10.1016/j.yexcr.2007.05.006

Cited by 25 publications

(20 citation statements)

References 14 publications

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“…It is well established that, in cancer, iASPP has an oncogenic function, and in several cancer cell lines its experimental silencing promotes apoptosis (Cai et al, 2012;Jiang et al, 2011;Liu et al, 2009;Liu et al, 2008;Pang et al, 2010;Zhang et al, 2011). However, our data are consistent with a previous report that, in non-transformed cells (primary cultures of lymphocytes and fibroblasts), treatment with iASPPspecific siRNA reduced levels of apoptosis (Laska et al, 2007). Moreover, iASPP depletion reduces cell proliferation Chikh et al, 2011;Li et al, 2011;Lu et al, 2010;Notari et al, 2011;Zhang et al, 2011), and it is known that slowly proliferating cells are more resistant to cytotoxic agents than rapidly proliferating cells (Sultana et al, 2003).…”

Section: Discussionsupporting

confidence: 92%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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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.

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Section: Discussionsupporting

confidence: 92%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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“…These proteins stand for conserved characteristics of their structure and share similarity in C‐terminal sequence containing ankyrin repeats, the SH3 domain, and a proline‐rich region. ASPP family members can bind to some key proteins in controlling apoptosis and cell growth, such as p53, BCL‐2, APCL, PP1, and RelA/p65, which confer on them the ability to regulate the apoptotic function of p53 (8, 9). iASPP is the most evolutionary conserved member of ASPP family.…”

mentioning

confidence: 99%

“…them the ability to regulate the apoptotic function of p53 (8,9). iASPP is the most evolutionary conserved member of ASPP family.…”

mentioning

confidence: 99%

Oncogene iASPP enhances self‐renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation

et al. 2014

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iASPP is a member of the apoptosis-stimulating proteins of p53 (ASPP) family and negatively regulates the apoptotic function of p53. In a hematopoietic system, overexpression of iASPP results in blockage of apoptosis, which may play a role in regulating hematopoietic stem cell (HSC) numbers. To address this, we first analyzed the expression of iASPP in patients with acute leukemia (AL) and found it was highly expressed in patients with AL. We further established a transgenic mouse model in which human iASPP was specifically expressed in hematopoietic cells. Overexpression of iASPP led to an increase in the proportion of long-term HSCs, short-term HSCs, multipotent progenitors, and common myeloid progenitor. HSCs from iASPP transgenic mice had an advantage in long-term reconstitution potential. In addition, the hematopoietic cells from iASPP transgenic mice exhibited a significantly lower level of p53 dependent apoptosis. After irradiation damage, hematopoietic cells of iASPP transgenic mice had a higher level of γ-H2AX expression, which lasted for a longer time. These results provide the first evidence that the iASPP can increase HSC populations and reconstitution capacity. Interestingly, in response to cell damage stimuli, hematopoietic cells can be protected against apoptosis by iASPP; meanwhile these apoptosis-resistant cells would have more mutation accumulation, which might be the potential risk for malignant transformation.-Jia, Y., Peng, L., Rao, Q., Xing, H., Huai, L., Yu, P., Chen, Y., Wang, C., Wang, M., Mi, Y., Wang, J. Oncogene iASPP enhances self-renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation.

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“…iASPP, as the important inhibitor of p53, was found to facilitate cancer progression in more cancer recently [18,19]. iASPP was considered as an oncogene that not only inhibited the transactivation function of p53 on the promoters by binding with p53, but also promoted carcinogenesis through p53-independent mechanisms [20][21][22].The overexpression of iASPP in primary mouse embryonic fibroblasts promoted p53 degradation Fig. 5 Effects of VP16 on the expression of P53, P21, Puma, Bcl-2, PARP, cleaved-PARP, caspase3 and cleaved-caspases3 in K562, K562-iASPP hi and K562-Dou hi cells.…”

Section: Discussionmentioning

confidence: 99%

Sertad1 Antagonizes iASPP Function By Hindering Its Entrance into Nuclei to Interact with P53 in Leukemic Cells

Qiu

et al. 2014

Blood

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Introduction: As the important suprressor of P53, iASPP was found to be overexpressed in leukemia, and functioned as oncogene that inhibited apoptosis of leukemia cells. Sertad1 is identified as one of the proteins that can bind with iASPP in our previous study by two-hybrid screen. Sertad1 is highly expressed in carcinomas from pancreatic, lung and ovarian tissues, which considered Sertad1 as an oncoprotein. In this study, our findings revealed that Sertad1 could interact with iASPP in the cytoplasm near nuclear membrane, which could block iASPP to enter into nucleus to interact with P53, and inhibited the function of iASPP eventually. Methods: Co-immunoprecipitation and fluorescence confocal microscopic imaging were used to confirm the interaction between iASPP and Sertad1, the exact binding domains and the subcellular colocalization.The plasmids of iASPP and Sertad1 were transfected alone or co-transfected into K562 cells, the stable subclones that highly expressed iASPP, Sertad1 or both of them were then established by limiting dilution and named as K562-iASPPhi, K562-Sertad1hi, and K562-Douhi, respectively. The cell proliferation, cell cycle and apoptosis of above subclones were investigated by flow cytometry. Further, silence of the above two proteins was performed to confirm their functions. Immunoblotting analysis and immunofluorescence were performed to explore the possible mechanisms of difference between the biological functions of the above subclones. Results: Sertad1 expression level varied in leukemic cell lines and AML patients irrespectively of iASPP and P53. Interaction between iASPP and Sertad1 did exist in 293 cell and leukemic cells, both iASPP and Sertad1 scattered in the cytoplasm and nucleus, and their colocalizations were mainly in the cytoplasm, which encircled the nucleus. iASPP binds directly to Sertad1 through its PHD-bromo domain, C-terminal domain and Cyclin-A domain in a reduced order, and Serta domain failed to bind to iASPP. Overexpression of iASPP in K562 cells (iASPPhi) could result in the increased cell proliferation, cell cycle arrest in G2/M phase and resistance to apoptosis induced by chemotherapy drugs. While overexpression of iASPP and Sertad1 at the same time (Douhi) could slow down the cell proliferation, lead the cells more vulnerable to the chemotherapy drugs. As figure showed, in K562-Douhi cells, both iASPP and Sertad1 were obviously located in the cytoplasm, which encircled the nuclei, the subcellular colocalization was nearly outside the nuclei. The immunoblotting analysis further supported the conclusions. The resistance of iASPP to chemotherapeutic drug was accompanied by Puma protein expression in a p53-independent manner. By knocking down the expersssion of iASPP and Sertad separately, we found that iASPP is dispensable for maintenance of anti-apoptotic function and Sertad1 is indispensable for cell cycle in leukemic cells. Conclusions: In normal situation, the protein iASPP and Sertad1 scatter in the nucleus and cytoplasm, mainly in the cytoplasm. As convinced by our study, iASPP was overexpressed in the leukemia cell lines and primary AML patients, it could function as oncogene through its binding with P53 protein in the nucleus, inhibit the function of P53. When iASPPhi cells were exposed to apoptosis stimuli, Puma protein could play an important role in this process, irrespective of the expression level of P53. But when iASPP and Sertad1 were both overexpressed in the leukemic cells, Sertad1 could tether iASPP outside the nucleus mainly through its PHD-bromo domain, prevent it from inhibiting P53 function, suppress the leukemic cell growth and stimulate cell apoptosis by rescuing the P53 eventually. Our data provided a new insight to overcome iASPP protein, namely through its binding partners, when the similar proteins or drugs that can tether iASPP outside the nucleus such as Sertad1 are transfected into the leukemic cells, it may restore p53 function to eliminate the leukemic cells. Figure 1 Figure 1. Disclosures Wang: Novartis: Consultancy; Bristol Myers Squibb: Consultancy.

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Expression of the RAI gene is conducive to apoptosis: Studies of induction and interference

Cited by 25 publications

References 14 publications

iASPP is a novel autophagy inhibitor in keratinocytes

iASPP is a novel autophagy inhibitor in keratinocytes

Oncogene iASPP enhances self‐renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation

Sertad1 Antagonizes iASPP Function By Hindering Its Entrance into Nuclei to Interact with P53 in Leukemic Cells

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