pRb or its cousins: Who controls the family business?

Comment on: Bazarov A, et al. Cell Cycle 2012; 11:1008–1013More than 90% of human cancers are of epithelial origin. Cellular senescence of human mammary epithelial cells (HMECs) is an important barrier that protects cells from immortalization; the first step in breast cancer development.¹ Although induction of tumor suppressor p16 is not evident in some types of normal human fibroblasts undergoing senescence,² in cultured HMECs, senescence occurs by a robust p16 induction, and cells that acquire silencing of p16Ink4a locus eventually proliferate and undergo senescence again by telomere shortening in a p53-dependent manner.¹ Therefore, p16 induction is a critical barrier to immortalize HMECs in culture. p16 inhibits kinase activity of Cdk4/6-cyclinD complexes, which inactivate three pRb family proteins: pRb, p107 and p130. However, the relative contribution of these three pRb family proteins to HMEC senescence is not well understood.In a recent issue of Cell Cycle, Bazarov et al. examined the role of each pRb family protein in p16-mediated senescence in breast cancer cell lines and in HMECs (Fig. 1).³ They showed that knockdown of each of the three pRb family proteins individually did not abrogate senescence mediated by ectopically expressed p16 in the breast cancer cell lines MDA-MB-231 and MCF7. However, the senescence induced by ectopic p16 was abrogated if they introduced E7, which inactivates all three pRb family proteins. Their data suggest that two of pRb family proteins can compensate for the loss of each pRb family protein to induce p16-mediated senescence in these cancer cells. The remaining question is whether all three pRb family members play an additive role, and whether the inactivation of at least two members of the pRb family is required to overcome p16-induced senescence in breast cancer cells. On the other hand, they showed that abrogation of pRb, but not of p107 and/ or p130, attenuates senescence in HMECs, suggesting a non-redundant critical role of pRb in HMEC senescence. These data are consistent with a recent report demonstrating that pRb has a non-redundant role in repressing DNA replication during H-ras-induced senescence of human fibroblasts,⁴ and explain why pRb, but not p107 or p130, is frequently mutated in cancer. Interestingly, although abrogation of pRb is critical for HMECs escaping senescence, simultaneous depletion of pRb together with either p107, p130 or both accelerates bypass of senescence. This suggests that p107 and p130 help pRb to trigger/maintain HMEC senescence in culture and possibly in vivo. Although each pRb family protein preferentially binds to different members of the E2F family,⁵ the contribution of each E2F family protein in escaping p16-mediated senescence remains unclear. Therefore, it will be interesting to see whether the critical role of pRb, and a supportive role of p130 and p107, in p16-mediated HMEC senescence depend on how each pRb family protein interacts with an E2F family protein.Open in a separate windowFigure 1. Contribution of pRb family proteins to p16-mediated senescence in breast cancer cells and HMECs. Knockdown of each of the three pRb family proteins in breast cancer cells does not abrogate ectopic p16-induced senescence, suggesting that either two of pRb family proteins can compensate for the loss of each pRb family proteins or all three of pRb family proteins play an additive role in p16-mediated senescence in breast cancer cells. On the other hand, knockdown of pRb, but not of p107 or p130, abrogates HMEC senescence, suggesting a non-redundant critical role for pRb in senescence of HMECs. However, the knockdown of either p107 or p130, in conjunction with pRb depletion, abrogates HMEC senescence more efficiently than pRb knockdown alone. This suggests a supporting role for p107 and p130 in maintaining HMEC senescence.Bazarov et al. also showed that even aggressive p53-negative breast cancer cells undergo cellular senescence upon ectopic p16 expression. These results are quite encouraging from an epigenetic therapy point of view. Silencing of p16 often occurs in breast cancer cells via promoter methylation. During DNA replication, cells require new p16 promoter methylation to keep p16 silenced. The observations of Bazarov et al. suggest that we may be able to stop the growth of even aggressive p53-negative breast cancers in patients by inducing p16 expression in cancer cells using DNA methylation inhibitors. Back to the question of running family business: “it appears that pRb is still the boss, but in some cases, it may get a helping hand from his cousins- p107 and p130.”     

Nutrigenomics-based personalised nutritional advice: in search of a business model?

Nutritional advice has mainly focused on population-level recommendations. Recent developments in nutrition, communication, and marketing sciences have enabled potential deviations from this dominant business model in the direction of personalisation of nutrition advice. Such personalisation efforts can take on many forms, but these have in common that they can only be effective if they are supported by a viable business model. The present paper takes an inventory of approaches to personalised nutrition currently available in the market place as its starting point to arrive at an identification of their underlying business models. This analysis is presented as a unifying framework against which the potential of nutrigenomics-based personalised advice can be assessed. It has uncovered nine archetypical approaches to personalised nutrition advice in terms of their dominant underlying business models. Differentiating features among such business models are the type of information that is used as a basis for personalisation, the definition of the target group, the communication channels that are being adopted, and the partnerships that are built as a part of the business model. Future research should explore the consumer responses to the diversity of “archetypical” business models for personalised nutrition advice as a source of market information on which the delivery of nutrigenomics-based personalised nutrition advice may further build.     

Transnationalism or assimilation? Patterns of sociopolitical adaptation among Canadian business immigrants

This study analyses patterns of sociopolitical incorporation among immigrant entrepreneurs in Ontario who entered Canada under the auspices of the federal Business Immigration Program [BIP] between 1984 and 1994. The analysis focuses specifically on issues of transnationalism, adaptation to mainstream social and political institutions, and citizenship. In-depth interviews of a sample of BIP entrepreneurs reveal that, over a period of eight to eighteen years, respondents generally achieved a high level of political awareness, maintained weak transnational ties, and naturalized at an extraordinarily high rate. In the process of sociopolitical integration, respondents relied primarily on human forms of capital, especially English language proficiency and business skills, rather than on the social capital that inheres in ethnic communities and networks.     

The business of biodiversity – What is needed for biodiversity markets to work

There has been considerable discussion in Australia about market-based initiatives with the potential to bring effective incentives and greater investment for farmers and other land managers to promote biodiversity conservation. These initiatives include biodiversity trading markets (also termed the nature repair market), stewardship schemes, certification programmes, sustainability frameworks, and natural capital accounting. We welcome these discussions and believe these initiatives would be true advances if they bring much greater investment in conservation and stronger protection and recovery of biodiversity. However, we also have major concerns about the integrity and scientific credibility of some of these initiatives. In this article, we discuss why it is critical that such initiatives both carefully define biodiversity and determine what elements of biodiversity are to be targeted in conservation efforts. We also discuss the fundamental importance of appropriate and agreed biodiversity metrics, as well as the critical need for rigorous, well designed and independent biodiversity monitoring. To ensure that initiatives like biodiversity trading markets, stewardship schemes, certification programmes, sustainability frameworks and natural capital accounting are rigorous, non-corruptible and actually deliver what they are intended to do, they will need to be underpinned by appropriate programme designs. This includes robust and transparent governance structures, high-quality monitoring and timely reporting of key metrics.     

Three decades in transport business: studies of metabolite transport in chloroplasts – a personal perspective

This article gives an historical overview of our group's research on various metabolite translocators of chloroplasts, such as the translocators for phosphorylated intermediates of the Calvin–Benson cycle and of glycolysis, of ADP and ATP, of dicarboxylates, of pyruvate and of hexoses; how it began and where it led to. Wherever appropriate, references will be made to research in other laboratories. This revised version was published online in June 2006 with corrections to the Cover Date.     

Sustainability criteria and indicators of bioenergy systems from steering,research and Finnish bioenergy business operators’ perspectives

This paper addresses the interface of steering, research, and business operators’ perspectives to bioenergy sustainability. Although bioenergy business operators are essential for sustainable development of bioenergy systems through implementation of sustainability criteria, their perspective to sustainability is rarely studied. We systematically studied the relevant sustainability criteria and indicators from the three perspectives in different stages of a general bioenergy life cycle and in different sustainability dimensions, and evaluated bioenergy operators’ sustainability principles, criteria and indicators simultaneously with respect to the steering and research data and a business sustainability maturity framework. We collected data from literature and a workshop for Finnish bioenergy experts. The results show a similar division of steering and operators’ sustainability criteria and indicators to life cycle stages and sustainability dimensions with a slight emphasis on business economic sustainability from operators’ perspective. The acceptability principle could provide bioenergy operators a meaningful way of identifying the role of sustainability criteria and indicators from steering and research sources in advancing their business sustainability maturity.     

“Who’s the face?”: communication and white identity in a Texas business community

This article examines the relationship between whiteness and communication through analysing how white business community members acknowledge their own, usually invisible, white identity. Discourse analysis of interactions in a Texas organization shows how white members construct white identity as intersecting with Texan, masculine, age and professional identity categories. Members mark the overt construction of white identity as a dispreferred action through using disclaimers, formulations, pauses, humour and non-racial terms. Analysis of minority business member talk illustrates how minorities orient to white members’ talk as exclusive towards minorities because they do not overtly and directly discuss race and because they orient to regional identity in a way that ignores racial diversity among Texans. Thus while white members attempt to acknowledge their raced position in the Texas business community, their communicative actions repeatedly index white identities and reproduce the hegemonic position of white, male, Texan professional identities in this community.     

Morgenröthe or business as usual: a personal account of the 2nd Annual EULAR Congress, Prague

The 2nd Annual European League Against Rheumatism (EULAR) Congress, held in Prague, 13–16 June 2001, was an impressive event with a record turnout of 8300 delegates. It offered a large variety of first-class state of the art lectures by some 180 invited worldwide speakers. Several new and ongoing therapeutic developments were discussed. The aim to attract the young scientific community was only partly achieved, and the dependence on industry posed some problems. The organization, however, was a big improvement compared with the previous congress in this series. The number of submitted abstracts was relatively low (1200) compared with the number of delegates. Accommodation of satellite symposia and organization of poster sessions remain problem areas of this meeting. The Annual EULAR Congress emerges as one of the two most important annual congresses of rheumatology, the other being the American College of Rheumatology meeting.     

How we do business (or, Why does it take other journals so long to review your paper?)

Have you ever wondered why it takes so long to get comments back from reviewers at some journals? After all, how long should it take to review a paper? I suspect most of us have asked this question at one time or another. While recently contemplating this, I thought it was time to tell you a little about how we run Autophagy, and at the same time compare it to the practices at some other journals where I have, on occasion (notably before the start of Autophagy), sent my own papers.     

How green are supported ‘green’ business models? Time for the life cycle approach to enter public support programmes

The International Journal of Life Cycle Assessment - ‘Green’ business models1 have received considerable political and financial support, which for the public is a validation of the...