Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

The cell cycle is controlled by numerous mechanisms ensuring correct cell division. This review will focus on these mechanisms, i.e. regulation of cyclin-dependent kinases (CDK) by cyclins, CDK inhibitors and phosphorylating events. The quality checkpoints activated after DNA damage are also discussed. The complexity of the regulation of the cell cycle is also reflected in the different alterations leading to aber- rant cell proliferation and development of cancer. Consequently, targeting the cell cycle in general and CDK in particular presents unique opportunities for drug discovery. This review provides an overview of deregulation of the cell cycle in cancer. Different families of known CDK inhibitors acting by ATP competition are also discussed. Cur- rently, at least three compounds with CDK inhibitory activity (flavopiridol, UCN-01, roscovitine) have entered clinical trials.

/pdf/the-cell-cycle-a-review-of-regulation-deregulation-and-1hym0zcxik.pdf

The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer

The pathologies of many infectious, autoimmune and malignant diseases are influenced by the profiles of cytokine production in pro-inflammatory (TH1) and anti-inflammatory (TH2) T cells. Interindividual differences in cytokine profiles appear to be due, at least in part, to allelic polymorphism within regulatory regions of cytokine gene. Many studies have examined the relationship between cytokine gene polymorphism, cytokine gene expression in vitro, and the susceptibility to and clinical severity of diseases. A review of the findings of these studies is presented. An on-line version featuring appropriate updates is accessible from the World Wide Web site, http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm.

/pdf/cytokine-gene-polymorphism-in-human-disease-on-line-mb7yqxfth5.pdf

Cytokine gene polymorphism in human disease: on-line databases.

The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.

/pdf/human-telomerase-and-its-regulation-12t8at67i9.pdf

Human Telomerase and Its Regulation

In the past few years, there has been a virtual explosion of information on the viral and bacterial molecules now known as superantigens. Some structures have been defined and the mechanism by which they interact with MHC class II and the V beta region of the T cell receptor is being clarified. Data are accumulating regarding the importance of virally encoded superantigens in infectivity, viral replication, and the life cycle of the virus. In the case of MMTV, evidence also suggests that superantigens encoded by a provirus may be maintained by the host to protect against future exogenous MMTV infection. Experiments in animals have also begun to elucidate the dramatic and variable effects of superantigens on responding T cells and other immune processes. Finally, the role of superantigens in certain human diseases such as toxic shock syndrome, some autoimmune diseases like Kawasaki syndrome, and perhaps some immunodeficiency disease such as that secondary to HIV infection is being addressed and mechanisms are being defined. Still, numerous important questions remain. For example, it is not clear how superantigens with such different structures, for example, SEB, TSST-1, and MMTV vSAG, can interact with MHC and a similar region of the TCR in such basically similar ways. It remains to be determined whether there are human equivalents of the endogenous murine MMTV superantigens. The functional role of bacterial superantigens also remains to be explained. Serious infection and serious consequences from toxin-producing bacteria are relatively rare events, and it is questionable whether such events are involved in the selection pressure to maintain production of a functional superantigen. Hypotheses to explain these molecules, which can differ greatly in structure, include T cell stimulation-mediated suppression of host responses or enhancement of environments for bacterial growth and replication, but substantiating data for these ideas are mostly absent. It also seems likely that only the tip of the iceberg has been uncovered in terms of the role of superantigens in human disease. Unlike toxic shock syndrome, other associations, especially with viral superantigens, may be quite subtle and defined only after considerable effort. The definition of these molecules and mechanisms of disease may result in new therapeutic strategies. Finally, it is apparent that superantigens have dramatic effects on the immune system. One wonders whether these molecules or modifications of them can be used as specific modulators of the immune system to treat disease.

Superantigens and their potential role in human disease.

C.B-17 scid mice were reconstituted by intraperitoneal injection of human tonsil cells or PBL from EBV-seronegative donors. Subsequent injection of EBV resulted in the rapid development (within 19-33 d) of aggressive, fatal, lymphoproliferative disorders of human B cell origin. Autopsies revealed solid tumors in the abdomen, and occasionally in the liver, thymus, or spleen. Histopathologic analysis showed that the tumors were high-grade immunoblastic lymphomas and FACS analyses of tumor cells indicated that they were of human B-lymphoid origin. The tumor cells grew in vitro and induced new tumors on injection into severe combined immunodeficient (SCID) mice. Karyotypic analysis and Southern blots for c-myc or bcl-2 rearrangements revealed no chromosomal abnormalities and translocations. Southern blot analysis also showed that the cells possessed EBV DNA sequences. Although these tumors undoubtedly reflect infection of the transferred B cells with EBV in vivo, intraperitoneal transfer of short-term lymphoid cell lines transformed in vitro with EBV resulted in ascites production without evidence of tumor formation.

/pdf/epstein-barr-virus-induces-aggressive-lymphoproliferative-20a244rsn0.pdf

Epstein-Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice.

Interferon α down-regulates telomerase reverse transcriptase and telomerase activity in human malignant and nonmalignant hematopoietic cells

Sjogren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands. These patients have a markedly increased frequency of developing non-Hodgkin's lymphoma in their salivary glands and cervical lymph nodes. Translocations of proto-oncogene bcl-2 t(14;18) were observed in five of seven SS-associated lymphomas by Southern blot analysis. Using primers specific for chromosomes 14 and 18, translocation of the proto-oncogene bcl-2 was detected by polymerase chain reaction (PCR) in all five lymphomas positive by Southern blot analysis. Among SS patients lacking clinical evidence of coexistent lymphoma, no bcl-2 translocations were detected in 50 consecutive salivary gland biopsies. Of particular interest, pre-lymphoma biopsies were available from the seven SS patients who subsequently developed lymphoma and these DNA samples lacked detectable t(14;18) translocations even though they exhibited oligoclonal rearrangements of their immunoglobulin genes. We conclude that the great sensitivity of PCR can help us in detecting early onset of lymphoma in SS patients and aid in understanding the transition from autoimmunity to lymphoma.

/pdf/high-frequency-of-t-14-18-translocation-in-salivary-gland-15f7pitxha.pdf

High frequency of t(14;18) translocation in salivary gland lymphomas from Sjögren's syndrome patients.

In the pathogenesis of Sjogren's syndrome (SS), a role for Epstein-Barr virus (EBV) has been suggested because; (a) EBV is present in salivary gland epithelial cells of healthy individuals, and exaggerated immune responses against EBV could play a role in the destruction of salivary glands in SS; (b) SS salivary gland biopsies contain increased levels of EBV DNA compared to normal salivary glands, indicating viral reactivation and inability of lymphoid infiltrates to control EBV replication in patients with SS; and (c) salivary gland epithelial cells in patients with SS express high levels of HLA-DR antigens and may present EBV associated antigens to immune T cells in patients with SS. Therefore, SS may represent a situation where genetically predisposed individuals (i.e., HLA-DR3-DQA4-DQB2) have a persistent but ineffectual T cell immune response against EBV at its site of latency. In the case of rheumatoid arthritis (RA), evidence for a potential role of EBV includes the following: (a) EBV encoded proteins share antigenic and sequence similarity to proteins found in the synovial tissues. These crossreactive proteins include EBV protein gp110 (BALF-4) and the beta chain of HLA-DR4. Also, the human and mycobacterial 65 kDa heat shock proteins have a sequence similar to that of EBV encoded proteins; (b) patients with RA have increased frequency and levels of antibodies against specific epitopes on EBV encoded EBNA-1 (BKRF-1) and EBNA-3 (BERF-1) antigens; and (c) lymphocytes from patients with RA have decreased ability to limit outgrowth of autologous EBV infected lymphocytes, probably due to defects in release of interferon gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Pavel Pisa

Papers

Epstein-Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice.

Interferon α down-regulates telomerase reverse transcriptase and telomerase activity in human malignant and nonmalignant hematopoietic cells

High frequency of t(14;18) translocation in salivary gland lymphomas from Sjögren's syndrome patients.

Potential role of Epstein-Barr virus in Sjögren's syndrome and rheumatoid arthritis.

Cyclin E overexpression in relapsed adult acute lymphoblastic leukemias of B-cell lineage