Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development. Signals exchanged between neighboring cells through the Notch receptor can amplify and consolidate molecular differences, which eventually dictate cell fates. Thus, Notch signals control how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs. Notch activity affects the implementation of differentiation, proliferation, and apoptotic programs, providing a general developmental tool to influence organ formation and morphogenesis.

http://science.sciencemag.org/content/sci/284/5415/770.full.pdf

Notch Signaling: Cell Fate Control and Signal Integration in Development

Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences

Proliferation, cell cycle and apoptosis in cancer

mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery

MYC on the Path to Cancer

Much has been written about the functions of the E2F transcription factor and the product of the retinoblastoma tumor suppressor gene (pRB). These proteins have been described in terms that vary from ‘‘master regulators of cell cycle and differentiation’’ to ‘‘peripheral factors that lie outside the core cell cycle machinery.’’ Most often, pRB and E2F are described in short and simple terms as opposing molecules that control the G1to Sphase transition. There is an element of truth in each of these descriptions. E2Fand pRB-family proteins clearly play important roles in cell proliferation and differentiation. The extent to which they are master regulators or peripheral factors is a question of semantics, and these terms tell us more about the writer than the proteins. Perhaps the most important development in the E2F literature is the appreciation that E2F and pRB are not unique molecules with functions that can be defined in black and white terms. Instead, E2F and pRB represent families of related proteins that have diverse and occasionally contradictory activities. We now know a great deal about E2F complexes and pRB-family proteins and the emerging picture defies a one-line explanation. The fascinating variety of activities ascribed to various E2F complexes challenges us to place these into context and to find the right perspective. This review is presented into two sections. The first section summarizes the tremendous progress into the composition and properties of E2F and the many interactions that coordinately regulate E2F-dependent transcription. The rapid growth in the size of the E2F literature hides the fact that several fundamental questions have not been fully answered. Because of this, the second section of this review details five unresolved issues that have been highlighted by recent publications. It is impossible to cover all of the relevant E2F literature in a single review and readers are referred to reviews by Farnham (1995); Sardet et al. (1997); Helin (1998); and Yamasaki (1998) for a comprehensive survey.

http://genesdev.cshlp.org/content/12/15/2245.full.pdf

The regulation of E2F by pRB-family proteins

Coordination of Growth and Cell Division in the Drosophila Wing

Drosophila myc Regulates Cellular Growth during Development

http://www.imls.uzh.ch/static/CMS_publications/gallant/literatur/pdf/delaCova04Cell117-107.pdf

Drosophila Myc Regulates Organ Size by Inducing Cell Competition

Human neonatal lymphocytes produced little macrophage activation factor in response to mitogens. This correlated with decreased production of interferon-gamma (IFN gamma): adult lymphokines contained 894.2 +/- 177.1 U/ml, whereas neonatal cord and peripheral lymphokines contained 66.9 +/- 17.0 and 116.7 +/- 29.6 U/ml by bioassay. Results by radioimmunoassay (RIA) for IFN gamma were similar. In contrast, the interleukin 2 content of cord lymphokines was greater (P less than 0.01) and that of neonatal peripheral blood lymphokines similar to that of adults. Interleukin 1 production and interleukin 2 receptor expression and affinity were similar for adult and neonatal cells. Interleukins 1 and 2 in amounts comparable to those in adult lymphokines did not increase production of macrophage activation factor or IFN gamma by neonatal cells. Neonatal cells did not contain intracellular IFN or degrade exogenous IFN. Excess suppressor activity was not found in neonatal cultures. Addition of IFN alpha, 10,000-50,000 U/ml of interleukin 2 or phorbol myristate acetate (PMA) to cord mononuclear cells or of adult monocytes or PMA to cord T cells increased IFN gamma production compared to cells stimulated with concanavalin A (ConA) alone. Nevertheless, under optimal conditions (T cells + PMA + Con A), adult cells produced much more IFN gamma (1,360 +/- 261 U/ml by RIA) than cord cells (122 +/- 37 U/ml). Staphylococcal enterotoxin A (SEA) stimulated cord cell IFN gamma production at low cell densities; nevertheless, adult cells produced more IFN in response to SEA 1,341 +/- 350 U/ml) than cord cells (350 +/- 33 U/ml). Decreased production of IFN gamma by neonatal cells appears to be due both to differences in their intrinsic capacity to produce IFN gamma and to differences in regulatory mechanisms.

/pdf/decreased-production-of-interferon-gamma-by-human-neonatal-eb2lmadu55.pdf

Decreased production of interferon-gamma by human neonatal cells. Intrinsic and regulatory deficiencies.

In developing organs, the regulation of cell proliferation and patterning of cell fates is coordinated. How this coordination is achieved, however, is unknown. In the developing Drosophila wing, both cell proliferation and patterning require the secreted morphogen Wingless (Wg) at the dorsoventral compartment boundary (reviewed in ref. 1). Late in wing development, Wg also induces a zone of non-proliferating cells at the dorsoventral boundary. This zone gives rise to sensory bristles of the adult wing margin2,3. Here we investigate how Wg coordinates the cell cycle with patterning by studying the regulation of this growth arrest. We show that Wg, in conjunction with Notch, induces arrest in both the G1 and G2 phases of the cell cycle in separate subdomains of the zone of non-proliferating cells. Wg induces G2 arrest in two subdomains by inducing the proneural genes achaete and scute, which downregulate the mitosis-inducing phosphatase String (Cdc25)4. Notch activity creates a third domain by preventing arrest at G2 in wg-expressing cells, resulting in their arrest in G1.

Laura A. Johnston

Papers

Coordination of Growth and Cell Division in the Drosophila Wing

Drosophila myc Regulates Cellular Growth during Development

Drosophila Myc Regulates Organ Size by Inducing Cell Competition

Decreased production of interferon-gamma by human neonatal cells. Intrinsic and regulatory deficiencies.

Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing