Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dependence on Bcl-2 proteins is a common feature of cancer cells and provides a therapeutic opportunity. ABT-737 is an antagonist of antiapoptotic Bcl-2 proteins and therefore is a good predictor of Bcl-x(L)/Bcl-2 dependence. Surprisingly, analysis of Mcl-1-dependent multiple myeloma cell lines revealed codependence on Bcl-2/Bcl-x(L) in half the cells tested. Codependence is not predicted by the expression level of antiapoptotic proteins, rather through interactions with Bim. Consistent with these findings, acquired resistance to ABT-737 results in loss of codependence through redistribution of Bim to Mcl-1. Overall, these results suggest that complex interactions, and not simply expression patterns of Bcl-2 proteins, need to be investigated to understand Bcl-2 dependence and how to better use agents, such as ABT-737.
 ...
PMID:Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells. 2165 44

A block in apoptotic cell death is a likely requirement for cancer maintenance. Likewise, drug resistance, one of the key clinical problems in oncology, can often be explained by apoptotic resistance following drug administration. Several signalling pathways can commit cells to death, including intrinsic mitochondrial pathways controlled by the Bcl-2-like proteins, extrinsic Death Receptor-triggered pathways, and Dependence Receptor-initiated pathways. In addition, depending on the cell type, external stimulus and context, various other pro- or anti-survival signalling pathways may become repressed or activated. Proper coordination and conversion into a common cellular response is ensured by various ways of inter-pathway crosstalk. As for most signalling cascades, post-translational control of the signalling proteins involved is mainly achieved by reversible phosphorylation and thus by the coordinated actions of protein kinases and phosphatases. Despite increasing interest in phosphatases as potential tumour suppressors, their role in controlling apoptotic signalling remains poorly understood. Here we review current knowledge about the regulatory functions of Protein Phosphatase type 2A (PP2A) phosphatases in these apoptotic signalling networks. PP2A represents an abundant class of structurally complex Ser/Thr phosphatases which are of particular interest in this context because of their recently established role as genuine tumour suppressors. In line with these tumour suppressive characteristics, PP2A predominantly displays pro-apoptotic functions, although some PP2A complexes also clearly counteract apoptotic cell death. Finally, we speculate how this knowledge might be exploited for therapeutic purposes, in light of pre-clinical pharmacological approaches, currently demonstrated to target PP2A in cancer cells.
 ...
PMID:The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells. 2230 Jan 39

The p21-activated kinase (PAK) serine/threonine kinases are important effectors of the small GTPases Rac and Cdc42, and play significant roles in controlling cell growth, motility, and transformation. Knockdown of PAK4 or PAK1 inhibited the proliferation of mutant KRAS or BRAF colon cancer cells in vitro. Dependence on PAK4 or PAK1 protein for colon cancer cell proliferation was independent of PAK4 or PAK1 protein expression levels. Mutant KRAS HCT116 colorectal cells were the most sensitive to PAK4 or PAK1 knockdown resulting in the potent inhibition of anchorage-dependent and -independent proliferation as well as the formation and proliferation of HCT116 colon cancer spheroids. This inhibition of proliferation did not correlate with inhibition of RAF/MEK/ERK or PI3K/AKT signaling. In HCT116 cells, knockdown of PAK4 or PAK1 caused changes to the actin cytoskeleton resulting in reduced basal spread and cell elongation and increased cell rounding. These cytoskeletal rearrangements seemed to be independent of LIMK/cofilin/paxillin phosphorylation. PAK4 or PAK1 knockdown initially induced growth arrest in HCT116 cells followed by cell death at later time points. Inhibition of the antiapoptotic proteins Bcl-2 and Bcl-X(L) with the pharmacologic inhibitor ABT-737 increased effector caspase activation and apoptosis, and reduced cell survival with PAK4 or PAK1 knockdown. These results support a role for the PAKs in the proliferation of mutant KRAS-driven colorectal carcinoma cells via pathways not involving RAF/MEK/ERK and PI3K/AKT signaling.
 ...
PMID:Knockdown of PAK4 or PAK1 inhibits the proliferation of mutant KRAS colon cancer cells independently of RAF/MEK/ERK and PI3K/AKT signaling. 2323 84