Untitled

Abstract

An understanding of the complexity of cancer is important for correct diagnostics and efficient treatment of this disease. Recent developments of proteomics technologies allow us to address the complexity of tumorigenesis at a level of global protein profiling. This review discusses recent studies of signaling processes in cells of epithelial origin undertaken with the use of global protein profiling. Tumors of epithelial origin comprise about 90% of human breast cancers, and it is believed that transformation of breast epithelial cells shares common features of transformation with other mammalian cells: destabilization of the genome followed by acquisition of immortalization, unrestricted growth, evasion of death-inducing signals, and acquisition of invasive and tumor promoting characteristics. Functional proteomics of growth-promoting, growth-inhibiting, and pro-apoptotic signaling pathways, in combination with proteomics studies of breast epithelial cell differentiation and profiling of breast tumorigenesis, revealed groups of regulated proteins: structural components, stress-regulated proteins, regulators of transcription, translation and RNA processing, and regulators of posttranslational modifications, e.g., kinases, phosphatases, and proteases. The first lesson of proteomics studies is the discovery of significant number of new targets, as compared to total number of affected proteins. The second lesson is the poor correlation between expressions of proteins and their mRNAs. The third lesson is the low amplitude of protein changes compared to that observed for mRNA. These observations also recommend the analysis of signaling patterns rather than separate signaling pathways.

TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage

“…Smad proteins are mediators of the effect of transforming growth factor-b (TGFb) on expression of genes controlling proliferation and apoptosis of cells (de Caestecker et al, 2000;Derynck et al, 2001;Souchelnytskyi, 2002). TGFb binds to specific receptors with intrinsic serine/threonine kinase activity; upon ligand binding, a heterotetrameric complex of two type I and two type II receptors is formed, in which receptor kinases are activated and phosphorylate Smad3 and Smad2.…”

“…Mutations or functional inactivation of Smad2, Smad3 and Smad4 have been observed in leukemias, as well as in colorectal, breast and pancreatic cancers. Restoration of Smad activities in tumor cells with mutated Smads led to inhibition of the tumorigenic properties of cells (de Caestecker et al, 2000;Derynck et al, 2001;Souchelnytskyi, 2002;Siegel and Massague, 2003). Ablation of the Smad3 gene in mice has been reported to result in an enhanced colorectal tumorigenesis, albeit the tumorigenic effect appears to depend on the mouse strain used (Zhu et al, 1998).…”

Bridging proteomics and systems biology: What are the roads to be traveled?

“…As these PTMs are involved in crucial regulatory processes in cells, there is strong interest in their study. As an example, phosphorylation on serine, threonine and tyrosine residues are essential for regulation of cell proliferation, differentiation, migration and apoptosis [11,12,[32][33][34]. Initiation of signaling downstream of polypeptide growth factors such as EGF, TGFb, PDGF, TNFa and FGF, is dependent on activation of receptor tyrosine or serine/threonine kinases.…”

“…Most of the proteomics experiments with time frames longer than 24 h explore the long-term transformations of cells [95,96]. These effects may be related to cells of a selected type, e.g., exploring the differentiation of cells, or to cells in a context of multicellular organisms, e.g., the study of cells in a developing body.…”

“…These effects may be related to cells of a selected type, e.g., exploring the differentiation of cells, or to cells in a context of multicellular organisms, e.g., the study of cells in a developing body. This includes the profiling of various tissues and different cell lines that originate from the same tissue [95,96]. Thus, longer time frames in proteomics studies are associated with the larger complexity of the studied system (Fig.…”