The extracellular matrix (ECM) is a cell surface associated three-dimensional macromolecular network composed of collagens, proteoglycans/glycosaminoglycans, elastin, fibronectin, laminins, and several other glycoproteins. The network provides a dynamic microenvironment surrounding the cell enabling it to carry on its function.
Ubiquitinating enzymes (UBEs) catalyze protein ubiquitination, a reversible process countered by deubiquitinating enzyme (DUB) action . CYLD deubiquitinase regulates inflammation and cell proliferation by down regulating NF-κB signaling through removal of ubiquitin chains from several NF-κB pathway proteins .
Methylation of DNA at cytosine residues in mammalian cells is a heritable, epigenetic modification that is critical for proper regulation of gene expression, genomic imprinting and development (1,2). Three families of mammalian DNA methyltransferases have been identified: DNMT1, DNMT2, and DNMT3 (1,2).
Ataxia telangiectasia mutated kinase (ATM) and ataxia telangiectasia and Rad3-related kinase (ATR) are PI3 Kinase-related kinase (PIKK) family members that phosphorylate multiple substrates on serine or threonine residues that are followed by a glutamine in response to DNA damage or replication blocks (1-3). p53 is phosphorylated by ATM, ATR and DNA-PK at Ser15. This phosphorylation impairs the ability of MDM2 to bind p53, promoting both the accumulation and activation of p53 in response to DNA damage (4,5). Chk1 and Chk2, downstream protein kinases of ATM/ATR, plays an important role in DNA damage checkpoint control, embryonic development and tumor suppression (6).
The nucleosome, made up of four core histone proteins (H2A, H2B, H3, and H4), is the primary building block of chromatin. Originally thought to function as a static scaffold for DNA packaging, histones have now been shown to be dynamic proteins, undergoing multiple types of post-translational modifications, including acetylation, phosphorylation, methylation, and ubiquitination
The tumor necrosis factor receptor family, which includes TNF-RI, TNF-R2, Fas, DR3, DR4, DR5, and DR6, plays an important role in the regulation of apoptosis in various physiological systems. The receptors are activated by a family of cytokines that include TNF, FasL, TWEAK, and TRAIL. They are characterized by a highly conserved extracellular region containing cysteine-rich repeats and a conserved intracellular region of about 80 amino acids termed the death domain (DD). The DD is important for transducing the death signal by recruiting other DD containing adaptor proteins (FADD, TRADD, RIP) to the death-inducing signaling complex (DISC) resulting in activation of caspases.
Control of the cell cycle is regulated by a multitude of cellular events and processes. The cyclin dependent kinases (CDK) regulate many of these pathways and constitute an active complex when associated with their cyclin partners. This activity is controlled primarily by phosphorylation, which determines subcellular localization of the CDK/cyclin complex (1,2). Some phosphorylation events control the function of cytoplasmic retention sequences while other events regulate nuclear localization and export sequence function (3,4). Cyclin and cyclin-dependent kinase inhibitor (CKI) levels are regulated by ubiquitination and degradation via the ubiquitin proteasome pathway (5). A variety of CKI proteins associate with these complexes and modulate access to regulatory domains on cyclins (6). Additional complexity is generated as the controlled protein levels of each cyclin oscillate with the stages of cell cycle. Increased expression of Cyclin D1 is associated with certain types of cancer (7,8) and may associate with TSC2 (tuberin) independent of its Cdk partner (9).
Keratins (cytokeratins) are intermediate filament proteins that are mainly expressed in epithelial cells. Keratin heterodimers composed of an acidic keratin (or type I keratin, keratins K9-K28) and a basic keratin (or type II keratin, keratins K1-K8 and K71-K80) assemble to form filaments. Keratin isoforms demonstrate tissue- and differentiation-specific profiles that make them useful as research and clinical biomarkers.
The regulation of cell growth, differentiation and programmed death is coordinated by several sets of proteins that comprise essential signal transduction pathways. Many of these key regulatory proteins are encoded by proto-oncogenes, which can be activated (altered) to change the typical cell program to one of abnormal cell growth and unregulated development. Proteins encoded by proto-oncogenes include growth factors and other ligands, receptor proteins, tyrosine kinases, various regulatory proteins (i.e. GTPases) and transcription factors. Together these proteins comprise the basic elements of cell signaling pathways; altered expression or mutation of one or more of these components can lead to oncogenic growth.
