c-Abl Tyrosine Kinase Activates p21 Transcription Via Interaction with p53

Jing, Yuqi; Wang, Min; Tang, Wen; Qi, Tianyang; Gu, Chunsheng; Hao, Shui; Zeng, Xianlu

doi:10.1093/jb/mvm068

Cited by 14 publications

(7 citation statements)

References 24 publications

(34 reference statements)

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“…Altering the subcellular localisation of p53 can alter its biological functions (Moll et al, 2005). Our results showed that p53 was mainly retained in the nucleus after RAMP knockdown, indicating that p53 functioned as a transcription factor to increase the expression of p21 (McKenzie et al, 1999;Jiang et al, 2001;Jing et al, 2007) and promoted apoptosis (Yonish-Rouach et al, 1991;Lowe et al, 1993;Tsao et al, 1999). Moreover, the apoptosis induced by RAMP knockdown can be completely counteracted by RAMP/p53 double knockdown, but only partially abolished by RAMP/p21 double knockdown.…”

Section: Discussionmentioning

confidence: 71%

Identification of retinoic acid-regulated nuclear matrix-associated protein as a novel regulator of gastric cancer

et al. 2009

Br J Cancer

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BACKGROUND: Retinoic acid-regulated nuclear matrix-associated protein (RAMP) is a WD40 repeat-containing protein that is involved in various biological functions, but little is known about its role in human cancer. This study aims to delineate the oncogenic role of RAMP in gastric carcinogenesis. METHODS: RAMP expression was examined by real-time quantitative RT-PCR, immunohistochemistry and western blotting. Inhibition of RAMP expression was performed by siRNA-mediated knockdown. The functional effects of RAMP on cell kinetics were measured by cell viability assay, colony formation assay and flow cytometry. Cell lines stably expressing RAMP were established to investigate the oncogenic effects of RAMP in vitro. RESULTS: Ramp was readily expressed in all seven gastric cancer cell lines and was significantly increased in human gastric cancer tissues when compared with their adjacent non-cancerous tissues (Po0.001). In keeping with this, expression of RAMP protein was higher in gastric cancer tissues compared with their adjacent non-cancerous tissues, whereas moderate protein expression were noted in intestinal metaplasia. Knockdown of RAMP in gastric cancer cells significantly reduced cell proliferation (Po0.01) and soft agar colony formation (Po0.001), but induced apoptosis and G 2 /M arrest. In additional, knockdown RAMP induced cell apoptosis is dependent on functional accumulation of p53 and p21 and induction of cleaved caspases-9, caspases-3 and PARP. Strikingly, overexpression of RAMP promoted anchorage-independent cell growth in soft agar. CONCLUSION: Our findings demonstrate that RAMP plays an oncogenic role in gastric carcinogenesis. Inhibition of RAMP may be a promising approach for gastric cancer therapy.

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Section: Discussionmentioning

confidence: 71%

Identification of retinoic acid-regulated nuclear matrix-associated protein as a novel regulator of gastric cancer

et al. 2009

Br J Cancer

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“…Previous studies also demonstrate that c-ABL is a positive regulator of p53 [43], interacting with p53, which can activate its downstream target p21 [44]. Treatment of CML with imatinib impairs p53 accumulation and function [45].…”

Section: Discussionmentioning

confidence: 91%

Inhibition of MDM2 by Nilotinib Contributes to Cytotoxicity in Both Philadelphia-Positive and Negative Acute Lymphoblastic Leukemia

Zhang

Liu

et al. 2014

PLoS ONE

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Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor related to imatinib that is more potent than imatinib. Nilotinib is widely used to treat chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The present study identifies Mouse double minute 2 homolog (MDM2) as a target of nilotinib. In studying ALL cell lines, we found that the expression of MDM2 in both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) ALL cells was remarkably inhibited by nilotinib, in a dose- and time-dependent manner. Further studies demonstrated that nilotinib inhibited MDM2 at the post-translational level by inducing MDM2 self-ubiquitination and degradation. Nilotinib-mediated MDM2 downregulation did not result in accumulation and activation of p53. Inhibition of MDM2 in nilotinib-treated ALL cells led to downregulation of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP), a translational target of MDM2, resulting in activation of caspases. Inhibition of XIAP following nilotinib-mediated downregulation of MDM2 resulted in apoptosis of MDM2-expressing ALL; however, similar nilotinib treatment induced stronger apoptosis in Ph+/MDM2+ ALL than in Ph-/MDM2+ or Ph+/MDM2- ALL. The ALL cells that were Ph-/MDM2- were totally resistant to nilotinib. These results suggested that nilotinib can inhibit MDM2 and induce a p53-independent apoptosis pathway by downregulating XIAP; thus, nilotinib can treat not only Ph+, but also Ph- ALL patients whose cancer cells overexpress MDM2.

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“…The ABL1 DNA-binding domain is critical for its biological function (50), yet no classical DNA-binding motifs have been identified so far. The few ABL1 transcriptional targets identified include p21 and CSF1 (33, 51). Here we demonstrated that ABL1 binds to the promoter region of CSF1 and activates CSF1 gene transcription.…”

Section: Discussionmentioning

confidence: 99%

CSF1R Signaling Blockade Stanches Tumor-Infiltrating Myeloid Cells and Improves the Efficacy of Radiotherapy in Prostate Cancer

et al. 2013

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Radiotherapy is used to treat many types of cancer, but many treated patients relapse with local tumor recurrence. Tumor-infiltrating myeloid cells (TIMs), including CD11b (ITGAM)+F4/80 (EMR1)+ tumor-associated macrophages (TAMs) and CD11b+Gr-1 (LY6G)+ myeloid-derived suppressor cells (MDSCs), respond to cancer-related stresses and play critical roles in promoting tumor angiogenesis, tissue remodeling and immunosuppression. In this report, we employed a prostate cancer model to investigate the effects of irradiation on TAMs and MDSCs in tumor-bearing animals. Unexpectedly, when primary tumor sites were irradiated we observed a systemic increase of MDSCs in spleen, lung, lymph nodes and peripheral blood. Cytokine analysis showed that the macrophage colony-stimulating factor CSF1 increased by 2-fold in irradiated tumors. Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in prostate cancer patients, where serum levels of CSF1 increased after radiotherapy. Mechanistic investigations revealed the recruitment of the DNA damage-induced kinase ABL1 into cell nuclei where it bound the CSF1 gene promoter and enhanced CSF1 gene transcription. When added to radiotherapy, a selective inhibitor of CSF1R suppressed tumor growth more effectively than radiation alone. Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of TIMs which can limit the efficacy of radiotherapy. Further, they suggest that CSF1 inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes.

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c-Abl Tyrosine Kinase Activates p21 Transcription Via Interaction with p53

Cited by 14 publications

References 24 publications

Identification of retinoic acid-regulated nuclear matrix-associated protein as a novel regulator of gastric cancer

Identification of retinoic acid-regulated nuclear matrix-associated protein as a novel regulator of gastric cancer

Inhibition of MDM2 by Nilotinib Contributes to Cytotoxicity in Both Philadelphia-Positive and Negative Acute Lymphoblastic Leukemia

CSF1R Signaling Blockade Stanches Tumor-Infiltrating Myeloid Cells and Improves the Efficacy of Radiotherapy in Prostate Cancer

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