A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis
- University of California, Berkeley, United States
- University of Cambridge, United Kingdom
- University of California, San Francisco, United States
- Duke University, United States
- Center for Systems Biology, University of Texas at Dallas, United States
- The Third Military Medical University, China
- Northwestern University Feinberg School of Medicine, United States
Figures
Figure 1 with 1 supplement
miR-92 negatively regulates the mir-17-92 oncogenic activity in the Eμ-myc B-lymphoma model.
(A) The gene structure of the mir-17-92 polycistron and its mutated derivatives. Light colored boxes, pre-miRNAs; dark colored boxes, mature miRNAs. Homologous miRNA components are indicated by the …
Figure 1—figure supplement 1
Gene structure and evolutionary conservation of mir-17-92.
(A) A diagram represents the gene structure of mir-17-92 and its two mammalian homologs. The six mir-17-92 components are classified into four distinct miRNA families based on the seed sequence …
Figure 2
The miR-92 deficient mir-17-92 cooperates with c-Myc to promote highly aggressive B-lymphomas.
(A) The percentage of IgM positive and IgM negative B-lymphomas was calculated for each genotype (Eμ-myc/MSCV, n = 10; Eμ-myc/17-92, n = 9; Eμ-myc/17-92Δ92, n = 10; Eμ-myc/17-92Mut92, n = 10). (B) …
Figure 3 with 1 supplement
miR-92 enhances both c-Myc-induced apoptosis and c-Myc-induced proliferation.
(A) The schematic representation of the adoptive transfer model to evaluate the miR-92 effects on the Eμ-myc premalignant B-cells in vivo. (B) miR-92 overexpression enhances the apoptotic response …
Figure 3—figure supplement 1
miR-92 enhances c-Myc-induced apoptosis both in vitro and in vivo.
(A) miR-92 enhances the apoptotic response in the premalignant Eμ-myc B-cells in vivo. Using the Eμ-myc adoptive transfer model, we generated well-controlled Eμ-myc/MSCV and Eμ-myc/92 mice that were …
Figure 4 with 1 supplement
miR-92 induces apoptosis through the activation of the p53 pathway.
(A) The genes upregulated by miR-92 were enriched for the cell cycle pathway and the p53 pathway. Microarray analyses compared gene expression profiles of serum starved and 4-OHT treated R26MER/MER …
Figure 4—figure supplement 1
miR-92 overexpression triggers the activation of the p53 pathway.
(A) miR-92 overexpression in R26MER/MER MEFs induced several p53 target genes in addition to those described in Figure 3C, including mdm2, Gtse1 and Bid, but not p21. (B) Induction of p53 targets by …
Figure 5 with 1 supplement
miR-92 promotes the accumulation of c-Myc protein through repressing Fbw7.
(A) miR-92 enhances the accumulation of c-Myc protein in synchronized R26MER/MER MEFs (upper), as well as primary B-cells (lower). The miR-92 overexpression and the control R26MER/MER MEFs were …
Figure 5—figure supplement 1
miR-92 overexpression enhances c-Myc protein level by repressing Fbw7.
(A) miR-92 overexpression did not affect c-myc mRNA levels in two independent primary B-cells. (B) The c-Myc dosage determines the degree of c-Myc-induced apoptosis in R26MER/MER MEFs. When R26MER/ME…
Figure 6 with 1 supplement
The antagonistic interaction between miR-19 and miR-92 regulates the balance between proliferation and apoptosis.
(A) The schematic representation of the Eμ-myc adoptive transfer model to evaluate the functional interaction between miR-92 and miR-19 in vivo. Light colored boxes, pre-miRNAs; dark colored boxes, …
Figure 6—figure supplement 1
Functional antagonism between miR-19:miR-92 regulates the balance between proliferation and apoptosis.
(A) miR-19 antagonizes the apoptotic effects of miR-92 in vivo. miR-92 overexpression enhanced apoptosis in premalignant Eμ-myc bone marrow B-cells in vivo, while co-expression of miR-19 and miR-92 …
Figure 7
The miR-19:miR-92 antagonism is disrupted during malignant transformation.
(A and B) Compared to normal splenic B-cells, premalignant and malignant Eμ-myc B-cells favored a greater increase in mature miR-19 (miR-19a and miR-19b) than miR-92. The purified normal splenic …
Tables
Table 1
Flow cytometric immunophenotyping of Eμ-myc lymphomas with enforced expression of different mir-17-92 derivatives
https://doi.org/10.7554/eLife.00822.006| Genotype | n | Percentage (%) | Immunotype |
|---|---|---|---|
| Eμ-myc/MSCV | 4 | 40 | B220+, IgM−, CD19+, CD4−, CD8− |
| 6 | 60 | B220+, IgM+, CD19+, CD4−, CD8− * | |
| Eμ-myc/17–92 | 4 | 40 | B220+, IgM−, CD19+, CD4−, CD8− |
| 5 | 50 | B220+, IgM+, CD19+, CD4−, CD8− † | |
| 1 | 10 | B220−, IgM−, CD19−, CD4+, CD8+ | |
| Eμ-myc/17–92Mut92 | 7 | 70 | B220+, IgM−, CD19+, CD4−, CD8− |
| 3 | 30 | B220+, IgM+, CD19+, CD4−, CD8− ‡ | |
| Eμ-myc/1792Δ92 | 8 | 80 | B220+, IgM−, CD19+, CD4−, CD8− |
| 2 | 20 | B220+, IgM+, CD19+, CD4−, CD8− § |
-
*
1 out of 6 samples predominantly contains IgM+ cells, with a small percentage of IgM− cells.
-
†
3 out of 5 samples predominantly contain IgM+ cells, with a small percentage of IgM− cells.
-
‡
1 out of 3 samples predominantly contains IgM+ cells, with a small percentage of IgM− cells.
-
§
1 out of 2 samples predominantly contains IgM+ cells, with a small percentage of IgM− cells.
