Rap2b, a novel p53 target, regulates p53-mediated pro-survival function

Zhang, Xinyue; He, Yunlong; Lee, Kyoung Hwa; Dubois, Wendy; Li, Ziqing; Wu, Xiaolin; Kovalchuk, Alexander L.; Zhang, Weimin; Huang, Jing

doi:10.4161/cc.24364

Cited by 44 publications

(48 citation statements)

References 54 publications

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“…Rap2B exhibits weak transforming activity, which was observed using anchorage-independent growth assays, suggesting that Rap2B is not an oncogene by itself (1). This also suggests that targeting Rap2B may sensitize tumor cells to apoptosis induced by DNA damage (1). Unpublished data by the authors of the present study also confirmed that Rap2B is the direct target gene of p53, and has a p53-dependent pro-survival function.…”

Section: Rap2b As a Novel P53 Target Regulates The P53-mediated Prosupporting

confidence: 73%

“…Since its identification in 1990, Rap2B has elicited a considerable interest (1,10). The Rap2B gene, which has a conservative Rap domain, is located at the 3q25.2 region of the human chromosome (which has been extensively explored in previous studies on cancer), and has four expressed sequence tags (21,22).…”

Section: Identification and Biological Characteristics Of Rap2bmentioning

confidence: 99%

“…Using an integrative genomic approach, Zhang et al (1) identified Rap2B as a conserved p53-activated gene, which inhibited p53-mediated apoptosis following DNA damage. Upon DNA damage, p53 directly binds to the promoter of Rap2B and activates its transcription (1). Since the specificity of the gene determines the structure and function of the protein, the Rap2B protein is expected to exhibit a specific protein structure and function (23).…”

Section: Identification and Biological Characteristics Of Rap2bmentioning

confidence: 99%

“…Similarly to other Ras proteins, Rap2B is associated with the occurrence and development of tumors (1,87). Certain studies have reported an association between the function of Rap2B and the development of malignant tumors, and increasing evidence clearly confirms this association (1,87).…”

Section: Potential Mechanism Of Rap2b In Tumor Developmentmentioning

confidence: 99%

“…The Ras family small guanosine 5'-triphosphate (GTP)-binding protein Rap2B is a member of the Ras oncogene family (1). Ras proteins are known to be promoters of tumorigenesis, and their expression has been observed in a variety of human tumors (2).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Structure, functional regulation and signaling properties of Rap2B

Qu¹,

Huang²,

Di³

et al. 2016

Oncology Letters

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Abstract. The Ras family small guanosine 5'-triphosphate (GTP)-binding protein Rap2B is is a member of the Ras oncogene family and a novel target of p53 that regulates the p53-mediated pro-survival function of cells. The Rap2B protein shares ~90% homology with Rap2A, and its sequence is 70% identical to other members of the Rap family such as RaplA and RaplB. As a result, Rap2B has been theorized to have similar signaling effectors to the GTPase-binding protein Rap, which mediates various biological functions, including the regulation of sterile 20/mitogen-activated proteins. Since its identification in the early 1990s, Rap2B has elicited a considerable interest. Numerous studies indicate that Rap2B exerts specific biological functions, including binding and stimulating phospholipase C-ε and interferon-γ. In addition, downregulation of Rap2B affects the growth of melanoma cells. The present review summarizes the possible effectors and biological functions of Rap2B. Increasing evidence clearly supports the association between Rap2B function and tumor development. Therefore, it is conceivable that anticancer drugs targeting Rap2B may be generated as novel therapies against cancer.

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Section: Rap2b As a Novel P53 Target Regulates The P53-mediated Prosupporting

confidence: 73%

Section: Identification and Biological Characteristics Of Rap2bmentioning

confidence: 99%

Section: Identification and Biological Characteristics Of Rap2bmentioning

confidence: 99%

Section: Potential Mechanism Of Rap2b In Tumor Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Structure, functional regulation and signaling properties of Rap2B

Qu¹,

Huang²,

Di³

et al. 2016

Oncology Letters

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p53 Loss Increases the Osteogenic Differentiation of Bone Marrow Stromal Cells

Castro

Shin

et al. 2015

Stem Cells

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The tumor suppressor, p53, plays a critical role in suppressing osteosarcoma. Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) have been suggested to give rise to osteosarcomas. However, the role of p53 in BMSCs has not been extensively explored. Here, we report that p53 regulates the lineage choice of mouse BMSCs (mBMSCs). Compared to mBMSCs with wild type p53, mBMSCs deficient in p53 have enhanced osteogenic differentiation, but with similar adipogenic and chondrogenic differentiation. The role of p53 in inhibiting osteogenic lineage differentiation is mainly through the action of Runx2, a master transcription factor required for the osteogenic differentiation of mBMSCs. We find that p53 indirectly represses the expression of Runx2 by activating the microRNA-34 family, which suppresses the translation of Runx2. Since osteosarcoma may derive from BMSCs, we examined whether p53 has a role in the osteogenic differentiation of osteosarcoma cells and found that osteosarcoma cells with p53 deletion have higher levels of Runx2 and faster osteogenic differentiation than those with wild type p53. A systems biology approach reveals that p53-deficient mBMSCs are more closely related to human osteosarcoma while mBMSCs with wild type p53 are similar to normal human BMSCs. In summary, our results indicate that p53 activity can influence cell fate specification of mBMSCs, and provide molecular and cellular insights into the observation that p53 loss is associated with increased osteosarcoma incidence.

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Cell cycle arrest and apoptosis are not dependent on p53 prior to p53-dependent embryonic stem cell differentiation

Jaiswal

DePamphilis

2020

Stem Cells

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Previous efforts to determine whether or not the transcription factor and tumor suppressor protein p53 is required for DNA damage‐induced apoptosis in pluripotent embryonic stem cells (ESCs) produced contradictory conclusions. To resolve this issue, p53+/+ and p53−/− ESCs derived by two different methods were used to quantify time‐dependent changes in nuclear DNA content; annexin‐V binding; cell permeabilization; and protein expression, modification, and localization. The results revealed that doxorubicin (Adriamycin [ADR]) concentrations 10 to 40 times less than commonly used in previous studies induced the DNA damage‐dependent G2‐checkpoint and completed apoptosis within the same time frame, regardless of the presence or absence of p53, p21, and PUMA. Increased ADR concentrations delayed initiation of apoptosis in p53−/− ESCs, but the rates of apoptosis remained equivalent. Similar results were obtained by inducing apoptosis with either staurosporine inhibition of kinase activities or WX8 disruption of lysosome homeostasis. Differentiation of ESCs by LIF deprivation revealed p53‐dependent formation of haploid cells, increased genomic stability, and suppression of the G2‐checkpoint. Minimal induction of DNA damage now resulted in p53‐facilitated apoptosis, but regulation of pluripotent gene expression remained p53‐independent. Primary embryonic fibroblasts underwent p53‐dependent total cell cycle arrest (a prelude to cell senescence), and p53‐independent apoptosis occurred in the presence of 10‐fold higher levels of ADR, consistent with previous studies. Taken together, these results reveal that the multiple roles of p53 in cell cycle regulation and apoptosis are first acquired during pluripotent stem cell differentiation.

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Rap2b, a novel p53 target, regulates p53-mediated pro-survival function

Cited by 44 publications

References 54 publications

Structure, functional regulation and signaling properties of Rap2B

Structure, functional regulation and signaling properties of Rap2B

p53 Loss Increases the Osteogenic Differentiation of Bone Marrow Stromal Cells

Cell cycle arrest and apoptosis are not dependent on p53 prior to p53-dependent embryonic stem cell differentiation

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