The role of the CCN family of proteins in blood cancers

Haematopoiesis is the term used to describe the production of blood cells. This is a tightly regulated hierarchical system in which mature circulating blood cells develop from a small population of haematopoietic stem (HSC) and progenitor cells within the microenvironment of the bone marrow. Molecular and genetic abnormalities arising in these stem cells lead to a block in the normal programme of proliferation and differentiation and result in the development of the blood cancers known as the leukaemias and lymphomas. Recently the regulatory role of the bone marrow microenvironment or niche has also become increasingly recognised. The interface between the bone and bone marrow (endosteum) and the region surrounding the blood vessels (perivascular) provide distinct niches harbouring quiescent HSC or proliferative HSC respectively. Current chemotherapeutic regimes can often successfully target the proliferative HSC but disease relapse occurs due to residual quiescent HSC. Understanding these developmental and regulatory processes and the associated cell communication mechanisms are thus crucial to the development of new treatment strategies. The CCN family of proteins have been recognised to play a key role in all aspects of haematopoiesis.     

TRIM家族蛋白在病毒感染中作用的研究进展

三基序蛋白家族(tripartite motif,TRIM)是参与不同细胞功能的一大类具有E3泛素连接酶活性的蛋白质,在宿主抗病毒免疫应答中发挥着重要的作用。TRIM家族蛋白可通过提高宿主固有免疫应答或直接降解病毒蛋白发挥抗病毒活性;部分病毒有时也可利用TRIM家族蛋白调控细胞因子表达促进自身感染。本文综述了TRIM家族蛋白在病毒复制中的作用及相关机制的研究进展,为研究病毒感染机制提供参考。     

Primate lentivirus capsid sensitivity to TRIM5 proteins

Mammalian cells express several factors that inhibit lentiviral infection and that have been under strong selective pressure. One of these factors, TRIM5, targets the capsid protein of incoming retrovirus particles and inhibits subsequent steps of the replication cycle. By substituting human immunodeficiency virus type 1 capsid, we were able to show that a set of divergent primate lentivirus capsids was generally not susceptible to restriction by TRIM5 proteins from higher primates. TRIM5alpha proteins from other primates exhibited distinct restriction specificities for primate lentivirus capsids. Finally, we identified novel primate lentiviral capsids that are targeted by TRIMCyp proteins.     

An active TRIM5 protein in rabbits indicates a common antiviral ancestor for mammalian TRIM5 proteins

The recent identification of antiretroviral tripartite motif-bearing restriction factors that protect against retroviral infection has revealed a novel branch of innate immunity. The factors target the retroviral capsid and inhibit infectivity soon after the capsid has entered the cytoplasm by an incompletely characterized mechanism. Restriction is species specific. For example, TRIM5alpha from Old World monkeys, but not humans, restricts human immunodeficiency virus type 1 infection. Here, we identify an antiviral TRIM5 molecule in rabbits that is closely related to antiviral TRIM5 of both primates and cattle. We demonstrate that the rabbit TRIM5 protein is active against divergent retroviruses and leads to a strong block to viral DNA synthesis and infectivity. Furthermore, we show that antiviral activity is directed against the viral capsid and that human TRIM5 proteins are dominant negative to restriction in rabbit cells. We propose that the sequence and restriction characteristics conserved between restriction factors from primates, cattle, and rabbits indicate that these factors have evolved from a common ancestor with antiretroviral properties.     

TRIM family proteins: roles in proteostasis and neurodegenerative diseases

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer''s disease (AD), Parkinson''s disease (PD) and Huntington''s disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs.     

TRIM proteins regulate autophagy: TRIM5 is a selective autophagy receptor mediating HIV-1 restriction

The tripartite motif protein family (TRIM) constitutes a class of immune-regulated proteins with antiviral, immune, cancer, and other properties reminiscent of those ascribed to autophagy. We show that TRIMs have dual roles in autophagy: as regulators and as cargo receptors. As regulators, TRIMs nucleate the core autophagy machinery by acting as platforms that assemble ULK1 and BECN1 into a functional complex in preparation for autophagy. TRIMs also act as novel selective autophagy receptors as exemplified by TRIM5/TRIM5α, a known HIV-1 restriction factor with a hitherto poorly defined mode of action. TRIM5 recognizes and targets HIV-1 for autophagic destruction. TRIM5 interactions with mammalian Atg8 proteins are required for this effector function. This establishes TRIM family members as regulators of autophagy, explains the antiretroviral mechanism of TRIM5, and defines a new basis for selective autophagy.     

TRIM proteins regulate autophagy: TRIM5 is a selective autophagy receptor mediating HIV-1 restriction

The tripartite motif protein family (TRIM) constitutes a class of immune-regulated proteins with antiviral, immune, cancer, and other properties reminiscent of those ascribed to autophagy. We show that TRIMs have dual roles in autophagy: as regulators and as cargo receptors. As regulators, TRIMs nucleate the core autophagy machinery by acting as platforms that assemble ULK1 and BECN1 into a functional complex in preparation for autophagy. TRIMs also act as novel selective autophagy receptors as exemplified by TRIM5/TRIM5α, a known HIV-1 restriction factor with a hitherto poorly defined mode of action. TRIM5 recognizes and targets HIV-1 for autophagic destruction. TRIM5 interactions with mammalian Atg8 proteins are required for this effector function. This establishes TRIM family members as regulators of autophagy, explains the antiretroviral mechanism of TRIM5, and defines a new basis for selective autophagy.     

TRIM family proteins: retroviral restriction and antiviral defence

Members of the tripartite motif (TRIM) protein family are involved in various cellular processes, including cell proliferation, differentiation, development, oncogenesis and apoptosis. Some TRIM proteins display antiviral properties, targeting retroviruses in particular. The potential activity of TRIM19, better known as promyelocytic leukaemia protein, against several viruses has been well documented and, recently, TRIM5alpha has been identified as the factor responsible for the previously described Lv1 and Ref1 antiretroviral activities. There is also evidence indicating that other TRIM proteins can influence viral replication. These findings are reviewed here, and the possibility that TRIMs represent a new and widespread class of antiviral proteins involved in innate immunity is also considered.     

The role of TRIM25 in the occurrence and development of cancers and inflammatory diseases

The tripartite motif (TRIM) family proteins are a group of proteins involved in different signaling pathways. The changes in the expression regulation, function, and signaling of this protein family are associated with the occurrence and progression of a wide range of disorders. Given the importance of these proteins in pathogenesis, they can be considered as potential therapeutic targets for many diseases. TRIM25, as an E3-ubiquitin ligase, is involved in the development of various diseases and cellular mechanisms, including antiviral innate immunity and cell proliferation. The clinical studies conducted on restricting the function of this protein have reached promising results that can be further evaluated in the future. Here, we review the regulation of TRIM25 and its function in different diseases and signaling pathways, especially the retinoic acid-inducible gene-I (RIG-I) signaling which prompts many kinds of cancers and inflammatory disorders.     

Intracellular localization and domain organization of human TRIM41proteins

A human gene previously identified as a partial cDNA homologous to the gene of RET finger protein was characterized. Northern hybridization detected three messages of 3.3, 4.2, and 7.5kb. The coding sequences of the more abundant of the three messages, the 4.2 and the 3.3kb, were determined. The former encodes a 630 amino acid protein (TRIM41) and the latter a 518 amino acid protein (TRIM41). Green fluorescent protein (GFP) fusions of full-length TRIM41 and TRIM41 were both observed as speckles in the cytoplasm and the nucleus. The result was corroborated by Western analysis of cellular fractions. Results with GFP fusions of various segments of the TRIM41 proteins indicated that the nuclear transport of the proteins is mediated by an N-terminal segment common to both isoforms, but independent of a classical nuclear localization signal sequence.     

Functional interactions between ubiquitin E2 enzymes and TRIM proteins

The TRIM (tripartite motif) family of proteins is characterized by the presence of the tripartite motif module, composed of a RING domain, one or two B-box domains and a coiled-coil region. TRIM proteins are involved in many cellular processes and represent the largest subfamily of RING-containing putative ubiquitin E3 ligases. Whereas their role as E3 ubiquitin ligases has been presumed, and in several cases established, little is known about their specific interactions with the ubiquitin-conjugating E2 enzymes or UBE2s. In the present paper, we report a thorough screening of interactions between the TRIM and UBE2 families. We found a general preference of the TRIM proteins for the D and E classes of UBE2 enzymes, but we also revealed very specific interactions between TRIM9 and UBE2G2, and TRIM32 and UBE2V1/2. Furthermore, we demonstrated that the TRIM E3 activity is only manifest with the UBE2 with which they interact. For most specific interactions, we could also observe subcellular co-localization of the TRIM involved and its cognate UBE2 enzyme, suggesting that the specific selection of TRIM-UBE2 pairs has physiological relevance. Our findings represent the basis for future studies on the specific reactions catalysed by the TRIM E3 ligases to determine the fate of their targets.     

Origin and evolution of TRIM proteins: new insights from the complete TRIM repertoire of zebrafish and pufferfish

Tripartite motif proteins (TRIM) constitute a large family of proteins containing a RING-Bbox-Coiled Coil motif followed by different C-terminal domains. Involved in ubiquitination, TRIM proteins participate in many cellular processes including antiviral immunity. The TRIM family is ancient and has been greatly diversified in vertebrates and especially in fish. We analyzed the complete sets of trim genes of the large zebrafish genome and of the compact pufferfish genome. Both contain three large multigene subsets--adding the hsl5/trim35-like genes (hltr) to the ftr and the btr that we previously described--all containing a B30.2 domain that evolved under positive selection. These subsets are conserved among teleosts. By contrast, most human trim genes of the other classes have only one or two orthologues in fish. Loss or gain of C-terminal exons generated proteins with different domain organizations; either by the deletion of the ancestral domain or, remarkably, by the acquisition of a new C-terminal domain. Our survey of fish trim genes in fish identifies subsets with different evolutionary dynamics. trims encoding RBCC-B30.2 proteins show the same evolutionary trends in fish and tetrapods: they evolve fast, often under positive selection, and they duplicate to create multigenic families. We could identify new combinations of domains, which epitomize how new trim classes appear by domain insertion or exon shuffling. Notably, we found that a cyclophilin-A domain replaces the B30.2 domain of a zebrafish fintrim gene, as reported in the macaque and owl monkey antiretroviral TRIM5α. Finally, trim genes encoding RBCC-B30.2 proteins are preferentially located in the vicinity of MHC or MHC gene paralogues, which suggests that such trim genes may have been part of the ancestral MHC.     

Deregulation of ribosomal proteins in human cancers

The ribosome, the site for protein synthesis, is composed of ribosomal RNAs (rRNAs) and ribosomal proteins (RPs). The latter have been shown to have many ribosomal and extraribosomal functions. RPs are implicated in a variety of pathological processes, especially tumorigenesis and cell transformation. In this review, we will focus on the recent advances that shed light on the effects of RPs deregulation in different types of cancer and their roles in regulating the tumor cell fate.     

Role of motor proteins in human cancers

Motor proteins include several protein families (Kinesin, Dynein and Myosin) responsible for intracellular transport, intercellular communication, among other functions. In cancer cells, motor proteins along with microtubules (MT) and other tubulin and actin structures, are crucial for cell proliferation and invasion. The cBioPortal platform for Cancer Genomics database was queried for solid cancers in a combined cohort of 9204 patients with complete cancer genomics data. To assess the importance of motor proteins in cancer, copy number alterations (CNAs) and survival rates were analyzed in the combined dataset. Kinesin, Dynein, and Myosin families showed CNAs in 47%, 49%, and 57 % of patients, respectively, in at least one of their members. Survival analysis showed that CNAs in Kinesin and Dynein, families’ genes in the same patients were significantly correlated to decreased overall survival. These results added more evidence to previous literature highlighting the importance of motor proteins as a target in cancer therapy. Kinesin inhibitors could act by several mechanisms such as inhibiting spindle assembly or centrosome separation during mitosis, leading to cell cycle arrest and eventually apoptosis. Dynein inhibitors modulate Dynein’s activity and MT binding, inhibiting cell proliferation and invasion. Myosin inhibitors act by stabilizing MT, inducing cell cycle arrest and inhibiting invasiveness. Increasing the specificity of motor proteins targeting drugs could improve cancer therapy and patient survival.     

The roles of FOX proteins in virus-associated cancers

Forkhead box (FOX) proteins play a crucial role in regulating the expression of genes involved in multiple biological processes, such as metabolism, development, differentiation, proliferation, apoptosis, migration, invasion, and longevity. Deregulation of FOX proteins is commonly associated with cancer initiation, progression, and chemotherapeutic drug resistance in many human tumors. FOX proteins deregulate through genetic events and the perturbation of posttranslational modification. The purpose of the present review is to describe the deregulation of FOX proteins by oncoviruses. Oncoviruses utilize various mechanisms to deregulate FOX proteins, including alterations in posttranslational modifications, cellular localization independently of posttranslational modifications, virus-encoded miRNAs, activation or suppression of a series of cell signaling pathways. This deregulation can affect proliferation, metastasis, chemotherapy resistance, and immunosuppression in virus-induced cancers and help to chronic viral infection, development of gluconeogenic responses, and inflammation. Since the PI3K/Akt/mTOR signaling pathway is the upstream FOXO, suppressing it can cause FOXO function to return, and this can be one of the reasons for patients to recover from the infection of the viruses used to treat these inhibitors. Hence, FOX proteins could serve as prognosis markers and target therapy specifically in cancers caused by oncoviruses.     

Secreted frizzled related proteins: Implications in cancers

The Wnt (wingless-type) signaling pathway plays an important role in embryonic development, tissue homeostasis, and tumor progression becaluse of its effect on cell proliferation, migration, and differentiation. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signaling that act by binding directly to Wnt ligands or to Frizzled receptors. In recent years, aberrant expression of SFRPs has been reported to be associated with numerous cancers. As gene expression of SFRP members is often lost through promoter hypermethylation, inhibition of methylation through the use of epigenetic modifying agents could renew the expression of SFRP members and further antagonize deleterious Wnt signaling. Several reports have described epigenetic silencing of these Wnt signaling antagonists in various human cancers, suggesting their possible role as tumor suppressors. SFRP family members thus come across as potential tools in combating Wnt-driven tumorigenesis. However, little is known about SFRP family members and their role in different cancers. This review comprehensively covers all the available information on the role of SFRP molecules in various human cancers.