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Results: 6

1.
Figure 4

Figure 4. PSMC2Loss cells lack a PSMC2 reservoir. From: Cancer vulnerabilities unveiled by genomic loss.

A. Total PSMC2 levels (top) and Native PAGE immunoblot for PSMA1-6 (middle) in PSMC2Neutral and PSMC2Loss cells. B. Native PAGE immunoblot for PSMA1-6 in A2780 (left) and OVCAR8 (right) after inducible suppression or ectopic expression of PSMC2, respectively. C. Native PAGE 26S and 20S peptidase cleavage in PSMC2Neutral and PSMC2Loss cells. D. Native PAGE 26S and 20S peptidase cleavage in isogenic systems used in B. E. In vitro 26S proteasome activities in PSMC2Neutral and PSMC2Loss cells. Each point represents a cell line; dashed lines represent averages. F. In vitro 26S proteasome activities in isogenic systems used in B and D. G-H. Dose response curve for bortezomib in (G) A2780 cells with and without PSMC2 suppression and (H) OVCAR8 with and without ectopic V5-PSMC2 expression. See also Figure S4 and Table S7.

Deepak Nijhawan, et al. Cell. ;150(4):842-854.
2.
Figure 3

Figure 3. Threshold requirement for PSMC2. From: Cancer vulnerabilities unveiled by genomic loss.

A. PSMC2 levels among ovarian cancer cell lines. B. PSMC2 levels in cells that express an inducible shRNA that targets either PSMC2 or LacZ. C. Effects of PSMC2 suppression on proliferation. D. Relationship between PSMC2 mRNA expression and proliferation in PSMC2Neutral (left) and PSMC2Loss (right) cells. Data represents averages ± S.D. E. Schematic combining data from Fig 3D and S3D–E indicates that A2780 and OVCAR8 cells share a similar absolute threshold requirement for PSMC2 (dashed line). F. Cellular proliferation in A2780 cells with and without PSMC2 suppression after introduction of control, PSMC2, or PSMC5 siRNAs. Data are presented as averages +/− S.E.M. See also Figure S3 and Table S6.

Deepak Nijhawan, et al. Cell. ;150(4):842-854.
3.
Figure 2

Figure 2. PSMC2Loss cells are sensitive to PSMC2 suppression. From: Cancer vulnerabilities unveiled by genomic loss.

A. Comparison of gene dependence between three models of oncogene addiction and PSMC2. Cell lines were classified by mutation status for PIK3CA, BRAF, or KRAS (n=102 in each case) or PSMC2 copy-number (n=84). For each class, gene dependency scores reflect the sensitivity to the gene on which the categorization was based. Solid bars represent average scores. B. The effect of PSMC2 suppression on the proliferation of six ovarian cell lines. C. PSMC2 levels (left) and relative proliferation rates (right) among cells expressing different combinations of PSMC2 shRNA targeting the 3’ UTR and ectopic V5-PSMC2 expression. Data are presented as averages ± S.D. See also Figure S2 and Table S4–5.

Deepak Nijhawan, et al. Cell. ;150(4):842-854.
4.
Figure 5

Figure 5. Complex PSMC2 buffers PSMC2Neutral cells against PSMC2 suppression. From: Cancer vulnerabilities unveiled by genomic loss.

A. Native PAGE immunoblot for PSMC2 across a panel of PSMC2Neutral and PSMC2Loss cells. B. Native PAGE immunoblot for PSMC2 in OVCAR8 and A2780 after ectopic expression or inducible suppression, respectively, of PSMC2. C. Quantification of 26S proteasome and ComplexPSMC2 levels after PSMC2 suppression in DoxshRNA- 2 A2780 cells by Native PAGE (top) and total PSMC2 levels (bottom). The four left lanes represent a standard curve derived from dilutions of lysate from cells cultured without doxycycline. 26Sproteasome and ComplexPSMC2 bands are shown at different exposures. D-F. OVCAR8 cells with and without PSMC2 suppression analyzed by Native PAGE immunoblots for (D) PSMA1-6 and (E) peptidase cleavage in lysates, and (F) total poly-ubiquitin levels (See also Fig S5A-B). G. ComplexPSMC2 contains PSMC2, PSMC1, PSMD2, and PSMD5. Immunoblots for 19S complex components in V5 immune complexes isolated from fractions (See also Fig S5C-D). See also Figure S5.

Deepak Nijhawan, et al. Cell. ;150(4):842-854.
5.
Figure 1

Figure 1. Identification of CYCLOPS genes. From: Cancer vulnerabilities unveiled by genomic loss.

A. The percentage of the cancer genome involved in copynumber loss. B. The fraction of deleted regions associated with deletion events of varying lengths. C. Biallelic inactivation of a tumor suppressor is often associated with a focal alteration of one copy (red bar) and hemizygous loss of all genes on the chromosome arm containing the other copy. D. Schematic describing the approach to identifying CYCLOPS genes. For each gene, we separated cell lines with and without loss of the gene and compared their dependency on that gene by permuting class labels. E. Frequency of hemizygous deletion, homozygous deletion, or DNA methylation of CYCLOPS and other genes. Data are presented as averages ± S.E.M. See also Figure S1 and Table S1–3.

Deepak Nijhawan, et al. Cell. ;150(4):842-854.
6.
Figure 6

Figure 6. Tumor-penetrating nanocomplex-mediated delivery of PSMC2-specific siRNA suppresses ovarian tumor growth. From: Cancer vulnerabilities unveiled by genomic loss.

A. Schematic depicting the mechanism of tumor-penetrating nanocomplex (TPN)-mediated delivery of siRNA. B. Comparison of cellular uptake of fluorescently labeled siRNA in untreated cells (solid grey) and cells treated with TPN alone (black line) and in combination with IgG (grey line) or an antibody to p32 (solid pink). C. Tumor burden of mice bearing disseminated OVCAR8 (top) or A2780 (bottom) orthotopic xenografts treated with TPN carrying either GFP-siRNA or PSMC2-siRNA. n=5 animals per group. D. PSMC2 levels in orthotopic tumors of A2780 or OVCAR8 after treatment with nanoparticles carrying siGFP or siPSMC2. E. Tumor burden of mice bearing orthotopic tumors of OVCAR8 cells expressing V5-PSMC2. n =5 animals per group. F. Tumor burden (top) and overall survival (bottom) of mice bearing orthotopic tumors of A2780 cells expressing doxycycline-inducible shRNA against PSMC2. n = 5–13 animals per group. Data in all panels presented as average ± S.E.M. Significance was determined by one-way ANOVA or Log-rank (Mantel-Cox) tests as appropriate. n.s. = not significant; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. See also Figure S6.

Deepak Nijhawan, et al. Cell. ;150(4):842-854.

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