Mammalian cells encode three D cyclins (D1, D2, and D3) that coordinately function as allosteric regulators of cyclin-dependent kinase 4 (CDK4) and CDK6 to regulate cell cycle transition from G1 to S phase. Cyclin expression, accumulation, and degradation, as well as assembly and activation of CDK4/CDK6 are governed by growth factor stimulation. Cyclin D1 is more frequently dysregulated than cyclin D2 or D3 in human cancers, and as such, it has been more extensively characterized. Overexpression of cyclin D1 results in dysregulated CDK activity, rapid cell growth under conditions of restricted mitogenic signaling, bypass of key cellular checkpoints, and ultimately, neoplastic growth. This review discusses cyclin D1 transcriptional, translational, and post-translational regulations and its biological function with a particular focus on the mechanisms that result in its dysregulation in human cancers.

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Cyclin D1, cancer progression, and opportunities in cancer treatment.

Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Regulation of the microbiome–brain–gut axis is essential for maintaining homeostasis, including that of the CNS. Moreover, there is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Research has focused on how the microbiota communicates with the CNS and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus, the concept of a microbiome–brain–gut axis is emerging which suggests that modulation of the gut microflora may be a tractable strategy for developing novel therapeutics for complex stress-related CNS disorders where there is a huge unmet medical need.

The Microbiome: Stress, Health and Disease

Highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) has developed strategies to inhibit host immune recognition. We identify cellular E3 ubiquitin ligase ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) as an interacting partner of the viral SARS-unique domain (SUD) and papain-like protease (PLpro), and, as a consequence, the involvement of cellular p53 as antagonist of coronaviral replication. Residues 95–144 of RCHY1 and 389–652 of SUD (SUD-NM) subdomains are crucial for interaction. Association with SUD increases the stability of RCHY1 and augments RCHY1-mediated ubiquitination as well as degradation of p53. The calcium/calmodulin-dependent protein kinase II delta (CAMK2D), which normally influences RCHY1 stability by phosphorylation, also binds to SUD. In vivo phosphorylation shows that SUD does not regulate phosphorylation of RCHY1 via CAMK2D. Similarly to SUD, the PLpros from SARS-CoV, MERS-CoV, and HCoV-NL63 physically interact with and stabilize RCHY1, and thus trigger degradation of endogenous p53. The SARS-CoV papain-like protease is encoded next to SUD within nonstructural protein 3. A SUD–PLpro fusion interacts with RCHY1 more intensively and causes stronger p53 degradation than SARS-CoV PLpro alone. We show that p53 inhibits replication of infectious SARS-CoV as well as of replicons and human coronavirus NL63. Hence, human coronaviruses antagonize the viral inhibitor p53 via stabilizing RCHY1 and promoting RCHY1-mediated p53 degradation. SUD functions as an enhancer to strengthen interaction between RCHY1 and nonstructural protein 3, leading to a further increase in in p53 degradation. The significance of these findings is that down-regulation of p53 as a major player in antiviral innate immunity provides a long-sought explanation for delayed activities of respective genes.

https://www.pnas.org/content/pnas/113/35/E5192.full.pdf

P53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLpro via E3 ubiquitin ligase RCHY1

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

The role of ubiquitin modification in the regulation of p53

Ubiquitylation is fundamental for the regulation of the stability and function of p53 and c-Myc. The E3 ligase Pirh2 has been reported to polyubiquitylate p53 and to mediate its proteasomal degradation. Here, using Pirh2 deficient mice, we report that Pirh2 is important for the in vivo regulation of p53 stability in response to DNA damage. We also demonstrate that c-Myc is a novel interacting protein for Pirh2 and that Pirh2 mediates its polyubiquitylation and proteolysis. Pirh2 mutant mice display elevated levels of c-Myc and are predisposed for plasma cell hyperplasia and tumorigenesis. Consistent with the role p53 plays in suppressing c-Myc-induced oncogenesis, its deficiency exacerbates tumorigenesis of Pirh2−/− mice. We also report that low expression of human PIRH2 in lung, ovarian, and breast cancers correlates with decreased patients' survival. Collectively, our data reveal the in vivo roles of Pirh2 in the regulation of p53 and c-Myc stability and support its role as a tumor suppressor.

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Elisabeth Tai

Papers

Role of Pirh2 in mediating the regulation of p53 and c-Myc.