Current Protein and Peptide Science - Volume 11, Issue 6, 2010

Cell numbers are regulated by a balance between proliferation and apoptosis (programmed cell death), and an accurate coordination between these two processes are essential for maintaining cellular homeostasis. However, dysregulation of proliferation and cell death processes are hallmarks that distinguish cancer from normal cells. In recent years, a number of proteins and pathways have been identified to be essential for maintaining the cell growth-death balance or for the development and progression of several human malignancies. These proteins and pathways therefore represent novel therapeutic targets for anticancer drug discovery. This special issue will focus on several “oncoproteins” (the proteins with tumor-inducing ability; including: Notch signaling pathway proteins, the Mammalian Target of Rapamycin/ mTOR, Phosphoinositide 3-Kinases/ PI3Ks, Epidermal Growth Family Receptor/ EGFR, and androgen receptor/ AR) or protein complexes (the 26S proteasome as an example) and “tumor suppressor proteins” (such as Moesin-ezrin-radixin-like protein/ Merlin). The selected articles highlight these proteins and their structures, folding, mutations, interactions with cofactors or hormones, cellular functions, and regulations by signal transduction, as well as crosstalk between some of these pathways. Furthermore, results of pharmaceutical or peptide-based inhibitors to specific protein structures have been summarized and the clinical significance of targeting these proteins for cancer treatment and prevention has been discussed. The opening article by Sarkar and colleagues discusses the novel Notch signaling pathway proteins that play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis. The authors review the structures and functions of notch signaling proteins and describe how deregulation of this pathway is involved in tumor development and progression, leading to metastasis and the ultimate demise of patients diagnosed with cancer. The authors also summarize the role of several Notch inhibitors, especially“natural agents” that could represent novel therapeutic strategies in targeting Notch signaling toward better treatment outcome of cancer patients. The complexes called “mammalian target of rapamycin” (mTOR) have attracted great attention recently due to the involvement of mTOR complexes in the development of various diseases including cancer, diabetes and obesity. Zhou and Huang discuss the advances in studies of the mTOR complexes, including mTOR interacting proteins, upstream regulators and downstream effectors, as well as the possibility of targeting mTOR complexes for cancer treatment and prevention. PI3Ks are oncogenic that coordinate various fundamental cellular responses including mitogenic signaling, proliferation, and vesicular trafficking. Overexpression of PI3Ks caused by genetic alterations has been frequently observed in different human cancers, suggesting that PI3Ks are suitable targets for therapeutic intervention. The article by Wu looks at recent progress in the study of PI3Ks and discusses several unique PI3Ks' oncogenic properties as well as their prognostic and therapeutic implications. Other oncoproteins, such as EGFR, play a vital role in regulating proliferation, differentiation, migration, angiogenesis, and cell death processes. Majumdar and co-authors review the involvement of EGFR in regulating events of gastrointestinal (GI) cancers during advancing age. The authors discuss current available therapeutics, such as targeting these receptors by peptidebased inhibitors or targeting GI cancer stem cells. The androgen receptor (AR) is another “oncoprotein” highlighted in this issue. AR is critical for proliferation of human prostate cancer cells, as both a transcription factor and an interacting protein with components of the pre-replication complex and DNA replication machinery. Reddy and co-authors review the newly identified role of AR protein in prostate cancer cell cycle regulation and discuss its interaction with some cell cycle regulatory proteins and enzymes of DNA synthesis. The authors propose that these interactions may enable AR to exert control over the process of DNA synthesis, and alterations in these AR-binding proteins may lead to the development of hormone-refractory prostate cancer. An in-depth understanding of the structural interactions between AR and cell cycle regulators may facilitate the development of new strategies for the treatment of prostate cancer. Protease complexes are also potential targets for cancer therapy. The ubiquitin-proteasome system plays an essential regulatory role in several critical cellular processes. It has been reported that human cancer cells possess elevated level of proteasome activity and are more sensitive to proteasome inhibitors than normal cells, indicating that the inhibition of the ubiquitin-proteasome system could be used as a novel approach for cancer therapy. The paper by Chen and Dou summarizes the structure and catalytic activities of the proteasome complexes, the properties and mechanisms of action of various proteasome inhibitors, and the clinical development of proteasome inhibitors as novel anticancer agents. Instead of focusing “oncoproteins” as in the above six reviews, the last article by Stamenkovic and Yu describes a tumor suppressor protein called Merlin, a protein encoded by the neurofibromatosis type 2 (NF2) tumor suppressor gene. Merlin regulates the cell-cell and cell-matrix adhesions. It also regulates functions of the cell surface adhesion/extracellular matrix receptors and plays important roles in stabilizing the contact inhibition of proliferation and in regulating activities of several receptor tyrosine kinases. The authors suggest that Merlin is a negative regulator of growth and progression of several non-NF2 associated cancer types and this translational research has potential impact for the treatment of cancer patients with altered Merlin functions or pathways.

Proteins and small peptides (growth factors and hormones) are key molecules in maintaining cellular homeostasis. To that end, Notch signaling pathway proteins are known to play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis, and thus it has been suggested that Notch may be responsible for the development and progression of human malignancies. Therefore, the Notch signaling pathway proteins may present novel therapeutic targets, which could have promising therapeutic impact on eradicating human malignancies. This review describes the role of Notch signaling pathway proteins in cancer and how its deregulation is involved in tumor development and progression leading to metastasis and the ultimate demise of patients diagnosed with cancer. Further, we summarize the role of several Notch inhibitors especially “natural agents” that could represent novel therapeutic strategies targeting Notch signaling toward better treatment outcome of patients diagnosed with cancer.

The mammalian target of rapamycin (mTOR) has attracted substantial attention because of its involvement in a variety of diseases, such as cancer, cardiac hypertrophy, diabetes and obesity. Current knowledge indicates that mTOR functions as two distinct multiprotein complexes, mTORC1 and mTORC2. mTORC1 phosphorylates p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and regulates cell growth, proliferation, and survival by integrating hormones, growth factors, nutrients, stressors and energy signals. In contrast, mTORC2 is insensitive to nutrients or energy conditions. However, in response to hormones or growth factors, mTORC2 phosphorylates Akt, and regulates actin cytoskeleton and cell survival. These findings not only reveal the crucial role of mTOR in physiology and pathology, but also reflect the complexity of the mTOR signaling network. In this review, we discuss the advances in studies of the mTOR complexes, including the interacting proteins, the upstream regulators and the downstream effectors of mTOR complexes, as well as their implication in certain human diseases.

Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that coordinate various fundamental cellular responses including mitogenic signaling, cell survival and proliferation, vesicular trafficking, cytoskeletal rearrangement and metabolism. Overexpression caused by genetic alterations such as the amplification or gain of copy numbers was frequently observed for various PI3Ks in different human cancers. In recent years, the high-frequency somatic mutations of PIK3CA observed in different human cancers further strengthen the notion that PI3Ks are optimal targets for therapeutic intervention. In this review, I summarize current experimental evidence about the transformation capability and oncogenic properties of different PIK3CA mutations identified in human cancers. I also discuss the association of PIK3CA mutations with other genetic markers, as well as the prognostic value of PIK3CA somatic mutations in human cancers. Finally, I discuss the application of PI3Ks as therapeutic targets in human cancers, including targeted and combinational therapies and the potential challenges that confront their clinical applications.

Cells of the gastrointestinal (GI) mucosa are subject to a constant process of renewal which, in normal adults, reflects a balance between the rates of cell production and cell loss. Detailed knowledge of these events is, therefore, essential for a better understanding of the normal aging processes as well as many GI diseases, particularly malignancy, that represent disorders of tissue growth. In general, many GI dysfunctions, including malignancy, increase with advancing age, and aging itself is associated with alterations in structural and functional integrity of the GI tract. Although the regulatory mechanisms for age-related increase in the incidence of GI-cancers are yet to be fully delineated, recent evidence suggests a role for epidermal growth factor receptors and its family members {referred to as EGFR(s)} in the development and progression of carcinogenesis during aging. The present communication discusses the involvement of EGFR(s) in regulating events of GI cancers during advancing age and summarizes the current available therapeutics targeting these receptors. The current review also describes the effectiveness of ErbB inhibitors as well as combination therapies. Additionally, the involvement of GI stem cells in the development of the age-related rise in GI cancers is emphasized.

The androgen receptor (AR) plays a critical role in proliferation and viability of prostate cancer cells. Therefore, suppressing AR activity by androgen deprivation or anti-androgen treatment has been the frontline therapy for over six decades. However, these treatment strategies are not curative and patients succumb to castration-resistant disease. Although AR is evidently critical for proliferation of prostate cancer cells, very little is known about its mechanism of action in this process. Over the years, the role of AR in prostate cancer cell proliferation and viability has been studied by focusing primarily on its role as a transcription factor. However, recent observations indicate that besides its role as a transcription factor, AR interacts physically with components of the pre-replication complex (pre-RC) and DNA replication machinery (replitase). These interactions may enable AR to exert control over the process of DNA synthesis. In addition, alterations in the proteins that interact with AR in complexes required for DNA synthesis could lead to the development of hormone-refractory prostate cancer. These observations suggest a paradigm shift for the role of AR in proliferation of prostate cancer cells from its role as a transcription factor to a non-transcriptional role as a component of the replication machinery, interacting with cell cycle regulatory proteins and enzymes of DNA synthesis. We propose that a detailed understanding of the structural interactions between AR and the components of pre-RC and replitase may lead to the development of new strategies for the treatment of prostate cancer.

Proteasomes are large multicatalytic proteinase complexes located in the cytosol and the nucleus of eukaryotic cells. The ubiquitin-proteasome system is responsible for the degradation of most intracellular proteins and therefore plays an essential regulatory role in critical cellular processes including cell cycle progression, proliferation, differentiation, angiogenesis and apoptosis. Besides involving in normal cellular functions and homeostasis, the alteration of proteasomal activity contributes to the pathological states of several clinical disorders including inflammation, neurodegeneration and cancer. It has been reported that human cancer cells possess elevated level of proteasome activity and are more sensitive to proteasome inhibitors than normal cells, indicating that the inhibition of the ubiquitin-proteasome system could be used as a novel approach for cancer therapy. In this review we summarize several specific aspects of research for the proteasome complex, including the structure and catalytic activities of the proteasome, properties and mechanisms of action of various proteasome inhibitors, and finally the clinical development of proteasome inhibitors as novel anticancer agents.

Genetic alterations of neurofibromatosis type 2 (NF2) gene lead to the development of schwannomas, meningiomas, and ependymomas. Mutations of NF2 gene were also found in thyroid cancer, mesothelioma, and melanoma, suggesting that it functions as a tumor suppressor in a wide spectrum of cells. The product of NF2 gene is merlin (moesinezrin- radixin-like protein), a member of the Band 4.1 superfamily proteins. Merlin shares significant sequence homology with the ERM (Ezrin-Radixin-Moesin) family proteins and serves as a linker between transmembrane proteins and the actin- cytoskeleton. Merlin is a multifunctional protein and involved in integrating and regulating the extracellular cues and intracellular signaling pathways that control cell fate, shape, proliferation, survival, and motility. Recent studies showed that merlin regulates the cell-cell and cell-matrix adhesions and functions of the cell surface adhesion/extracellular matrix receptors including CD44 and that merlin and CD44 antagonize each other's function and work upstream of the mammalian Hippo signaling pathway. Furthermore, merlin plays important roles in stabilizing the contact inhibition of proliferation and in regulating activities of several receptor tyrosine kinases. Accumulating data also suggested an emerging role of merlin as a negative regulator of growth and progression of several non-NF2 associated cancer types. Together, these recent advances have improved our basic understanding about merlin function, its regulation, and the major signaling pathways regulated by merlin and provided the foundation for future translation of these findings into the clinic for patients bearing the cancers in which merlin function and/or its downstream signaling pathways are impaired or altered.

Protein phosphorylation is the most ubiquitous post-translational modification (PTM), and plays important roles in most of biological processes. Identification of site-specific phosphorylated substrates is fundamental for understanding the molecular mechanisms of phosphorylation. Besides experimental approaches, prediction of potential candidates with computational methods has also attracted great attention for its convenience, fast-speed and low-cost. In this review, we present a comprehensive but brief summarization of computational resources of protein phosphorylation, including phosphorylation databases, prediction of non-specific or organism-specific phosphorylation sites, prediction of kinase-specific phosphorylation sites or phospho-binding motifs, and other tools. The latest compendium of computational resources for protein phosphorylation is available at: http://gps.biocuckoo.org/links.php