Oncogenic <i>K-RAS</i> Is Required to Maintain Changes in Cytoskeletal Organization, Adhesion, and Motility in Colon Cancer Cells

Pollock, Claire B.; Shirasawa, Senji; Sasazuki, Takehiko; Kölch, Walter; Dhillon, Amardeep S.

doi:10.1158/0008-5472.can-04-1911

Cited by 125 publications

(125 citation statements)

References 44 publications

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“…Indeed, expression of KrasV12 also increased the mechanical deformability of non-tumorigenic cells ( Figure 5D and Table 1). Similarly, knockout of a mutant Kras allele in colon tumor cells increased pMLC2 levels ( Figure 5E), as previously reported [20], and converted these mutant Kras-knockout cells into losers over their tumorigenic counterparts ( Figure 5F). Together, these data demonstrate that the activation of Kras influences entosis by inducing winner status.…”

Section: Oncogenic Kras Imparts Winner Status To Cellssupporting

confidence: 85%

Competition between human cells by entosis

et al. 2014

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Human carcinomas are comprised of complex mixtures of tumor cells that are known to compete indirectly for nutrients and growth factors. Whether tumor cells could also compete directly, for example by elimination of rivals, is not known. Here we show that human cells can directly compete by a mechanism of engulfment called entosis. By entosis, cells are engulfed, or cannibalized while alive, and subsequently undergo cell death. We find that the identity of engulfing ("winner") and engulfed ("loser") cells is dictated by mechanical deformability controlled by RhoA and actomyosin, where tumor cells with high deformability preferentially engulf and outcompete neighboring cells with low deformability in heterogeneous populations. We further find that activated Kras and Rac signaling impart winner status to cells by downregulating contractile myosin, allowing for the internalization of neighboring cells that eventually undergo cell death. Finally, we compute the energy landscape of cell-in-cell formation, demonstrating that a mechanical differential between winner and loser cells is required for entosis to proceed. These data define a mechanism of competition in mammalian cells that occurs in human tumors.

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Section: Oncogenic Kras Imparts Winner Status To Cellssupporting

confidence: 85%

Competition between human cells by entosis

et al. 2014

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“…However, TBP-1 immunoprecipitates contained Fra-1 species of differing mobilities on SDS-polyacrylamide gel electrophoresis gels, a likely indication that multiple phosphorylation states of the protein were present . In KRAS mutant HCT116 colon carcinoma cells, which express high levels of endogenous Fra-1 (Pollock et al, 2005), we found that endogenous TBP-1 was present in immunoprecipitates prepared using anti-Fra-1 but not control (IgG) antibodies (Figure 2b), and that only a small proportion of the TBP-1 in these cells was associated with Fra-1. In contrast to Fra-1, we found that c-Fos did not associate with TBP-1 in HEK293 cells (Figure 2c), indicating the capacity to interact with TBP-1 was not a property shared by all Fos family members.…”

Section: Resultsmentioning

confidence: 95%

“…Overexpression of the Fra-1 transcription factor in human cancers is strongly linked to tumour growth, migration and invasion Belguise et al, 2005;Debinski and Gibo, 2005;Pollock et al, 2005;Young and Colburn, 2006;Adiseshaiah et al, 2007;Doehn et al, 2009;Luo et al, 2010). Understanding the mechanisms regulating Fra-1 accumulation in tumour cells is a key issue, but one that is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…The Fos-related antigen-1 (Fra-1) is a Fos family member that is persistently overexpressed in a variety of cancers and tumour cell lines, where it has been reported to regulate cell proliferation, survival, migration and invasion Belguise et al, 2005;Debinski and Gibo, 2005;Pollock et al, 2005;Kakumoto et al, 2006;Young and Colburn, 2006;Adiseshaiah et al, 2007;Casalino et al, 2007;Doehn et al, 2009;Luo et al, 2010). A number of Fra-1-regulated genes have been implicated in these processes, including modulators of cell cycle progression (CCND1 and CCNA2; Burch et al, 2004;Casalino et al, 2007;Vikhanskaya et al, 2007), epithelial-mesenchymal transitions (ZEB1 and ZEB2; Shin et al, 2010, extracellular matrix degradation (MMP1 and MMP9;Kustikova et al, 1998) and migration (cd44, VEGF, c-met; Ramos-Nino et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

et al. 2011

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Fos-related antigen-1 (Fra-1) is a member of the Activator Protein-1 (AP-1) transcription factor superfamily that is overexpressed in a variety of cancers, including colon, breast, lung, bladder and brain. High Fra-1 levels are associated with enhanced cell proliferation, survival, migration and invasion. Despite its frequent overexpression, the molecular mechanisms that regulate the accumulation of Fra-1 proteins in tumour cells are not well understood. Here, we show that turnover of Fra-1, which does not require ubiquitylation, is cooperatively regulated by two distinct mechanisms-association with the 19S proteasomal subunit, TBP-1, and by a C-terminal degron, which acts independently of TBP-1, but is regulated by RAS-ERK (extracellular signal-regulated kinase) signalling. TBP-1 depletion stabilized Fra-1 and further increased its levels in tumour cells expressing RAS-ERK pathway oncogenes. These effects correlated with increased AP-1 transcriptional activity. We suggest that during Fra-1 degradation, association with TBP-1 provides a mechanism for ubiquitin-independent proteasomal recognition, while the C terminus of the protein regulates its subsequent proteolytic processing.

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“…In breast and colon carcinoma-or in glioblastoma-derived cell lines, Fra-1 knockdown resulted in prominent alterations in cell morphology and it altered the configuration and the distribution of actin filaments Belguise et al, 2005;Pollock et al, 2005;Debinski and Gibo, 2005). Fra-1 counteracted stress fibre formation by either reducing RhoA activity or interfering with this pathway downstream of Rho (Pollock et al, 2005), resulting in increased cell motility and decreased adhesion.…”

Section: Introductionmentioning

confidence: 99%

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

et al. 2011

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Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscleinvasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

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Oncogenic K-RAS Is Required to Maintain Changes in Cytoskeletal Organization, Adhesion, and Motility in Colon Cancer Cells

Cited by 125 publications

References 44 publications

Competition between human cells by entosis

Competition between human cells by entosis

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

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