N-terminal alanine-rich (NTAR) sequences drive precise start codon selection resulting in elevated translation of multiple proteins including ERK1/2.

We report the discovery of N-terminal alanine-rich sequences, which we term NTARs, that act in concert with their native 5'-untranslated regions to promote selection of the proper start codon. NTARs also facilitate efficient translation initiation while limiting the production of non-functional polypeptides through leaky scanning. We first identified NTARs in the ERK1/2 kinases, which are among the most important signaling molecules in mammals.

ERK1 and ERK2 Map Kinases: Specific Roles or Functional Redundancy?

The MAP kinase signaling cascade Ras/Raf/MEK/ERK has been involved in a large variety of cellular and physiological processes that are crucial for life. Many pathological situations have been associated to this pathway. More than one isoform has been described at each level of the cascade.

ERK1 and ERK2 present functional redundancy in tetrapods despite higher evolution rate of ERK1.

Background: The Ras/Raf/MEK/ERK signaling pathway is involved in essential cell processes and it is abnormally activated in ~30 % of cancers and cognitive disorders. Two ERK isoforms have been described, ERK1 and ERK2; ERK2 being regarded by many as essential due to the embryonic lethality of ERK2 knock-out mice, whereas mice lacking ERK1 are viable and fertile. The controversial question of why we have two ERKs and whether they have differential functions or display functional redundancy has not yet been resolved.

miR-483-3p controls proliferation in wounded epithelial cells.

The mechanisms that regulate keratinocyte migration and proliferation in wound healing remain largely unraveled, notably regarding possible involvements of microRNAs (miRNAs). Here we disclose up-regulation of miR-483-3p in 2 distinct models of wound healing: scratch-injured cultures of human keratinocytes and wounded skin in mice. miR-483-3p accumulation peaks at the final stage of the wound closure process, consistent with a role in the arrest of "healing" progression.

HIF-1alpha mediates the induction of IL-8 and VEGF expression on infection with Afa/Dr diffusely adhering E. coli and promotes EMT-like behaviour.

Microbes regulate a large panel of intracellular signalling events that can promote inflammation and/or enhance tumour progression. Indeed, it has been shown that infection of human intestinal cells with the Afa/Dr diffusely adhering E. coli C1845 strain induces expression of pro-angiogenic and pro-inflammatory genes.

HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration.

Epidermal wound repair is a complex process involving the fine orchestrated regulation of crucial cell functions, such as proliferation, adhesion and migration. Using an in vitro model that recapitulates central aspects of epidermal wound healing, we demonstrate that the transcription factor HIF1 is strongly stimulated in keratinocyte cultures submitted to mechanical injury. Signals generated by scratch wounding stabilise the HIF1alpha protein, which requires activation of the PI3K pathway independently of oxygen availability.

Microphthalmia-associated transcription factor regulates RAB27A gene expression and controls melanosome transport.

Melanosomes are lysosome-related organelles specialized in melanin synthesis and transport. In this study, we show that microphthalmia-associated transcription factor (MITF) silencing induces melanosome gathering around the nucleus and causes the relocalization of Rab27A, Slac2a-Mlph, and Myo5a that control the transport of melanosomes on the actin network. In an attempt to elucidate the mechanism by which MITF controls melanosome distribution, we identify RAB27A as a new MITF target gene.

Up-regulation of MET expression by alpha-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis.

The MET proto-oncogene encodes for the hepatocyte growth factor (HGF) receptor, a plasma membrane tyrosine kinase that is involved in melanocyte growth and melanoma development. In mouse melanoma cells, Met expression is increased by alphaMSH via the activation of the cAMP pathway. However, the mechanism by which cAMP regulates MET and the biological consequences of this increase were not known.

Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1/2, p38, and phosphatidylinositol 3-kinase signaling pathways.

Covering denuded dermal surfaces after injury requires migration, proliferation, and differentiation of skin keratinocytes. To clarify the major traits controlling these intermingled biological events, we surveyed the genomic modifications occurring during the course of a scratch wound closure of cultured human keratinocytes. Using a DNA microarray approach, we report the identification of 161 new markers of epidermal repair.

Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells.

In melanocytes and melanoma cells alpha-melanocyte stimulating hormone (alpha-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates Hif1a gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1alpha) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the Hif1a promoter and strongly stimulates its transcriptional activity.

Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophilin/Slac2-a and actin association.

Melanosomes are melanin-containing organelles that belong to a recently individualized group of lysosome-related organelles. Recently, numerous reports have dissected the molecular mechanisms that control melanosome transport, but nothing was known about the possible regulation of melanosome distribution by exogenous physiological stimulus. In the present report, we demonstrate that a physiological melanocyte-differentiating agent such as alpha-melanocyte-stimulating hormone, through the stimulation of the cAMP pathway, induces a rapid centrifugal transport of melanosomes, leading to their accumulation at the dendrite tips of melanocytes.

Microphthalmia-associated transcription factor (MITF) is required but is not sufficient to induce the expression of melanogenic genes.

Microphthalmia-associated transcription factor (MITF) plays a pivotal role in melanocyte survival and differentiation. Nevertheless, until now it has not been possible to show that MITF regulates the expression of the endogenous tyrosinase or Tyrp1. Further, a direct involvement of MITF in the regulation of melanin synthesis, a key parameter of melanocyte differentiation, remains to be demonstrated.

Interactions of human Myosin Va isoforms, endogenously expressed in human melanocytes, are tightly regulated by the tail domain.

Primary human epidermal melanocytes express six endogenous isoforms of the human actin-associated myosin Va motor protein, involved in organelle transport. As isoforms containing exon F are most abundant in melanocytes, we hypothesized that these isoforms probably have a melanocyte-specific function. To uncover the biologic role of the six isoforms we introduced enhanced green fluorescent protein (eGFP)-myosin Va tail constructs in human melanocytes.

Characterization of the molecular defects in Rab27a, caused by RAB27A missense mutations found in patients with Griscelli syndrome.

Rab27a plays a pivotal role in the transport of melanosomes to dendrite tips of melanocytes and mutations in RAB27A, which impair melanosome transport cause the pigmentary dilution and the immune deficiency found in several patients with Griscelli syndrome (GS). Interestingly, three GS patients present single homozygous missense mutations in RAB27A, leading to W73G, L130P, and A152P transitions that affect highly conserved residues among Rab proteins. However, the functional consequences of these mutations have not been studied.