Control of cell migration: a tumour suppressor function for p53?

Much remains to be learned about how cancer cells acquire the property of migration, a prerequisite for invasiveness and metastasis. Loss of p53 functions is assumed to be a crucial step in the development of many types of cancers, leading to dysregulation of cell cycle checkpoint controls and apoptosis. However, emerging evidence shows that the contribution of the tumour suppressor p53 to the control of tumorigenesis is not restricted to its well-known anti-proliferative activities, but is extended to other stages of cancer development, i.e. the modulation of cell migration. This interesting alternative function has been proposed in light of the effect of p53 on specific features of migrating cells, including cell spreading, establishment of cell polarization and the production of protrusions. The effects of p53 on cell motility are largely mediated through the regulation of Rho signalling, thereby controlling actin cytoskeletal organization. These recent studies connect the regulation of proliferation to the control of cell migration and define a new concept of p53 function as a tumour suppressor gene, suggesting that p53 might be involved in tumour invasion and metastasis. This review focuses on emerging data concerning the properties of p53 that contribute to its atypical role in the regulation of cell migration.     

p53: The Janus of autophagy?

The autophagy pathway functions in adaptation to nutrient stress and tumour suppression. The p53 tumour suppressor, previously thought to positively regulate autophagy, may also inhibit it. This dual interplay between p53 and autophagy regulation is enigmatic, but may underlie key aspects of metabolism and cancer biology.     

p16Ink4A,not only a G1 inhibitor?

Comment on: Chien WW, et al. Cell Cycle 2010; 9:3286-96.     

The p53-HAT connection: PCAF rules?

Comment on: Love IM, et al. Cell Cycle 2012; 11:2458-66.     

p16INK4a/p19Arf与年龄相关性胰岛β细胞功能

2型糖尿病是一种与年龄密切相关的疾病,随着年龄增加,胰岛β细胞增殖能力和分泌能力下降,糖尿病患病率明显增加,但其机制尚不清楚. 最近研究发现,细胞周期蛋白依赖激酶(cyclin-dependent kinase, CDK)抑制剂p16INK4a是引起胰岛β细胞年龄相关性老化的重要调控因子.研究表明,通过p16INK4a介导的胰岛老化机制可能有如下两个：p38MAPK(mitogen-activated protein kinase)途径和PDGFR(platelet-derived growth factor receptor) 途径,两者均引起p16ink4a及p19ARF表达增加,而损害胰岛细胞增殖.本文综述年龄相关性胰岛β细胞功能下降的潜在机制,从而为改善胰岛β细胞功能提供新的分子靶点.     

The spliceosome: a ribozyme at heart?

The spliceosome, the multi-megadalton molecular machine that performs splicing, consists of over 200 different proteins and five small nuclear RNAs (snRNAs). Extensive mechanistic and structural similarities to self-splicing group II introns, large ribozymes found in prokaryotes and lower eukaryotes that catalyze an identical reaction, strongly suggest that the spliceosomal RNAs are in fact the catalytic components of the spliceosome. Of the five spliceosomal RNAs, U2 and U6 are the only ones that are absolutely required for both steps of splicing. These two snRNAs form an elaborate base-paired complex that might in fact constitute the active site of the spliceosome.     

细胞衰老的重要通路:p16INK4a/Rb和p19ARF/p53/p21Cip1信号途径

细胞周期蛋白依赖激酶（cyclin-dependent kinase,CDK)抑制因子p16^INK4a,p21^Cipl等是细胞衰老的关键效应物。本文对涉及这些抑制物的两条衰老诱导途径作一综述,它们是p16^INK4a/Rb和p19^ARF/p53/p21^Cipl信号途径。其中,几个抑癌基因的产物R ,16^INFK4a,p53及p19^ARF处于两条途径的核心位置。     

Balancing selection at a frog antimicrobial peptide locus: fluctuating immune effector alleles?

Balancing selection is common on many defense genes, but it has rarely been reported for immune effector proteins such as antimicrobial peptides (AMPs). We describe genetic diversity at a brevinin-1 AMP locus in three species of leopard frogs (Rana pipiens, Rana blairi, and Rana palustris). Several highly divergent allelic lineages are segregating at this locus. That this unusual pattern results from balancing selection is demonstrated by multiple lines of evidence, including a ratio of nonsynonymous/synonymous polymorphism significantly higher than 1, the ZnS test, incongruence between the number of segregating sites and haplotype diversity, and significant Tajima's D values. Our data are more consistent with a model of fluctuating selection in which alleles change frequencies over time than with a model of stable balancing selection such as overdominance. Evidence for fluctuating selection includes skewed allele frequencies, low levels of synonymous variation, nonneutral values of Tajima's D within allelic lineages, an inverse relationship between the frequency of an allelic lineage and its degree of polymorphism, and divergent allele frequencies among populations. AMP loci could be important sites of adaptive genetic diversity, with consequences for host-pathogen coevolution and the ability of species to resist disease epidemics.     

The cell: locus or object of inquiry?

Research in many fields of biology has been extremely successful in decomposing biological mechanisms to discover their parts and operations. It often remains a significant challenge for scientists to recompose these mechanisms to understand how they function as wholes and interact with the environments around them. This is true of the eukaryotic cell. Although initially identified in nineteenth-century cell theory as the fundamental unit of organisms, researchers soon learned how to decompose it into its organelles and chemical constituents and have been highly successful in understanding how these carry out many operations important to life. The emphasis on decomposition is particularly evident in modern cell biology, which for the most part has viewed the cell as merely a locus of the mechanisms responsible for vital phenomena. The cell, however, is also an integrated system and for some explanatory purposes it is essential to recompose it and understand it as an organized whole. I illustrate both the virtues of decomposition (treating the cell as a locus) and recomposition (treating the cell as an object) with recent work on circadian rhythms. Circadian researchers have both identified critical intracellular operations that maintain endogenous oscillations and have also addressed the integration of cells into multicellular systems in which cells constitute units.     

Δ122p53, a mouse model of Δ133p53α, enhances the tumor-suppressor activities of an attenuated p53 mutant

Growing evidence suggests the Δ133p53α isoform may function as an oncogene. It is overexpressed in many tumors, stimulates pathways involved in tumor progression, and inhibits some activities of wild-type p53, including transactivation and apoptosis. We hypothesized that Δ133p53α would have an even more profound effect on p53 variants with weaker tumor-suppressor capability. We tested this using a mouse model heterozygous for a Δ133p53α-like isoform (Δ122p53) and a p53 mutant with weak tumor-suppressor function (mΔpro). The Δ122p53/mΔpro mice showed a unique survival curve with a wide range of survival times (92–495 days) which was much greater than mΔpro/- mice (range 120–250 days) and mice heterozygous for the Δ122p53 and p53 null alleles (Δ122p53/-, range 78–150 days), suggesting Δ122p53 increased the tumor-suppressor activity of mΔpro. Moreover, some of the mice that survived longest only developed benign tumors. In vitro analyses to investigate why some Δ122p53/mΔpro mice were protected from aggressive tumors revealed that Δ122p53 stabilized mΔpro and prolonged the response to DNA damage. Similar effects of Δ122p53 and Δ133p53α were observed on wild-type of full-length p53, but these did not result in improved biological responses. The data suggest that Δ122p53 (and Δ133p53α) could offer some protection against tumors by enhancing the p53 response to stress.The p53 tumor suppressor is most important for preventing cancers. p53 controls cell fate in response to stress by inducing apoptosis, cell cycle arrest/senescence, DNA repair (reviewed in Braithwaite et al.,^{1, 2} Oren,³ and Speidel⁴) or possibly restricting supply of basic substrates for metabolism.^{5, 6, 7} The regulation of p53 function has recently become more complex with the discovery of 13 isoforms, which may interfere with the normal functioning of full-length (FL) p53.^{8, 9, 10, 11, 12, 13, 14} An alternative promoter in intron 4 generates the Δ133p53 isoforms (Δ133p53α, and with additional alternative splicing in intron 9, Δ133p53β, and Δ133p53γ¹¹).The Δ133p53α isoform is expressed in many tissues, but elevated levels have been found in several cancers.^{11, 15, 16} Although the function(s) of Δ133p53α are not fully understood, growing evidence suggests it may have tumor-promoting capacities. Reducing Δ133p53α levels in the U87MG glioblastoma cell line reduced its ability to migrate and stimulate angiogenesis.¹⁷ Δ133p53α may also interfere with the tumor-suppressor functions of FLp53. The zebrafish ortholog of Δ133p53α, Δ113p53, inhibited p53-mediated apoptosis,¹⁸ and overexpression of Δ133p53α inhibited p53-directed G₁ cell cycle arrest.¹⁶Previously, we reported the construction and characterization of a mouse expressing an N-terminal truncation mutant of p53 (designated Δ122p53) that is very similar to Δ133p53α, providing the first mouse model of the Δ133p53α isoform.^{19, 20} Δ122p53 was found to increase cell proliferation and in p53 null cells transduced with a Δ122p53 expressing retrovirus, inhibited the transactivation of CDKN1a (encoding) p21^CIP1 and MDM2 by FLp53.^{19, 20} As well as elevating cell proliferation, homozygote Δ122p53 mice exhibited a profound pro-inflammatory phenotype, including increased serum interleukin-6 (IL-6) and γ-interferon (γ-IFN), and features of autoimmune disease.^{19, 20} The mice were tumor-prone displaying a complex tumor spectrum, but predominantly B-cell lymphomas and osteosarcomas. Thus, most evidence supports a role for the Δ133p53α isoform as a dominant oncogene that may interfere with normal FLp53 tumor-suppressor functions, but also has additional ''gain-of-function'' properties to promote tumor progression, probably through inflammatory mechanisms.²¹Given the above data, we reasoned that in an environment where p53 tumor-suppression capacity is compromised, such as in the context of the R72P allele^{22, 23, 24} or where p53 levels are reduced,^{25, 26, 27} the influence of Δ133p53α isoform on FLp53 function would be greater, leading to rapid tumor formation with a phenotype that would resemble that of the isoform alone. To test this, we generated mice heterozygous for Δ122p53 and a p53 mutant (mΔpro) that we previously described, that has attenuated tumor-suppressor activity.^{28, 29} The mΔpro mouse model is missing part of the p53 proline rich domain (PRD, amino acids 58–88). These mice are defective for DNA damage-induced apoptosis, and show a delayed and impaired cell cycle arrest response. Homozygous mΔpro mice develop late onset follicular B-cell tumors, while mΔpro heterozygotes developed few tumors in the presence of a wild-type p53 allele, or an early onset T-cell lymphoma in a p53-null background. In the latter case, the onset and tumor spectrum are indistinguishable from p53-null mice.²⁸In the current study, we found that, in contrast to our hypothesis, many Δ122p53/mΔpro mice showed extended survival compared with Δ122p53 homozygotes. In vitro analyses to explain this phenomenon suggested that Δ122p53 allele can enhance mΔpro tumor-suppressor functions, in particular cell cycle arrest.     

The viable but nonculturable phenotype: a crossroads in the life-cycle of non-differentiating bacteria?

In nature, prokaryotes must face alternating periods of prosperity and adversity. Differentiating bacteria confront situations of adversity by developing resistant structures. When there is a plentiful period, they adopt a vegetative state and when the period is adverse, a resistant structure, thereby completing a cycle. Non-differentiating bacteria do not develop such morphological distinct resistant structures. It has been proposed that many of these bacteria withstand periods of adversity by adopting the viable but nonculturable phenotype (VBNC). Bacteria of this phenotype conserve detectable metabolic function but become unculturable. Is it possible that the VBNC phenotype can revert to a culturable state, and vice versa, thus establishing a life-cycle? This review presents and evaluates different hypotheses regarding this question. Moreover, it attempts to analyse and proffer answers to other questions related to this phenotype. Is this a successful phenotype which prolongs survival? Is this a strategy for the survival of individual cells, or is it a strategy for the survival of a population? Finally, is it possible that this phenotype is, in fact, an example of altruistic death?