Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1

Myc plays a key role in homeostasis of the skin. We show that Miz1, which mediates Myc repression of gene expression, is expressed in the epidermal basal layer. A large percentage of genes regulated by the Myc-Miz1 complex in keratinocytes encode proteins involved in cell adhesion, and some, including the alpha6 and beta1 integrins, are directly bound by Myc and Miz1 in vivo. Using a Myc mutant deficient in Miz1 binding (MycV394D), we show that Miz1 is required for the effects of Myc on keratinocyte responsiveness to TGF-beta. Myc, but not MycV394D, decreases keratinocyte adhesion and spreading. In reconstituted epidermis, Myc induces differentiation and loss of cell polarization in a Miz1-dependent manner. In vivo, overexpression of beta1 integrins restores basal layer polarity and prevents Myc-induced premature differentiation. Our data show that regulation of cell adhesion is a major function of the Myc-Miz1 complex and suggest that it may contribute to Myc-induced exit from the epidermal stem cell compartment.     

Inhibition of the terminal stages of adipocyte differentiation by cMyc

The nuclear oncoprotein Myc is a pivotal regulator of several important biological processes, including cellular proliferation, differentiation, and apoptosis. Deregulated Myc expression is incompatible with terminal differentiation in a variety of cell types, including adipocytes. To understand how Myc inhibits adipogenesis, we analyzed the effect of Myc on the expression of genes characteristic of distinct phases of the hormonally induced adipogenic differentiation program in 3T3-L1 preadipocytes. We show that the early regulators, C/EBPbeta and C/EBPdelta, are induced normally in response to hormone in 3T3-L1 preadipocytes constitutively expressing Myc, but that expression of the downstream regulators, C/EBPalpha and PPARgamma2, and later markers of differentiation is suppressed. These data demonstrate that Myc specifically inhibits the terminal stages of the adipogenic program and suggest that Myc may act by blocking C/EBPbeta- and C/EBPdelta-directed activation of C/EBPalpha and PPARgamma2 expression, although the precise molecular mechanism is not understood. Surprisingly, a serum component(s) could override the Myc-induced differentiation block, suggesting that the ability of a cell to undergo terminal differentiation is governed by the action of both positive and negative factors. Since differentiation and proliferation are mutually exclusive events, this has important implications since it may be possible to force malignant cells along a differentiation pathway, thereby curbing their proliferative potential.     

Myc‐regulated microRNAs attenuate embryonic stem cell differentiation

Myc proteins are known to have an important function in stem cell maintenance. As Myc has been shown earlier to regulate microRNAs (miRNAs) involved in proliferation, we sought to determine whether c‐Myc also affects embryonic stem (ES) cell maintenance and differentiation through miRNAs. Using a quantitative primer‐extension PCR assay we identified miRNAs, including, miR‐141, miR‐200, and miR‐429 whose expression is regulated by c‐Myc in ES cells, but not in the differentiated and tumourigenic derivatives of ES cells. Chromatin immunoprecipitation analyses indicate that in ES cells c‐Myc binds proximal to genomic regions encoding the induced miRNAs. We used expression profiling and seed homology to identify genes specifically downregulated both by these miRNAs and by c‐Myc. We further show that the introduction of c‐Myc‐induced miRNAs into murine ES cells significantly attenuates the downregulation of pluripotency markers on induction of differentiation after withdrawal of the ES cell maintenance factor LIF. In contrast, knockdown of the endogenous miRNAs accelerate differentiation. Our data show that in ES cells c‐Myc acts, in part, through a subset of miRNAs to attenuate differentiation.     

Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb

The pocket protein family of tumor suppressors, and Rb specifically, have been implicated as controlling terminal differentiation in many tissues, including the heart. To establish the biological functions of Rb in the heart and overcome the early lethality caused by germ line deletion of Rb, we used a Cre/loxP system to create conditional, heart-specific Rb-deficient mice. Mice that are deficient in Rb exclusively in cardiac myocytes (CRbL/L) are born with the expected Mendelian distribution, and the adult mice displayed no change in heart size, myocyte cell cycle distribution, myocyte apoptosis, or mechanical function. Since both Rb and p130 are expressed in the adult myocardium, we created double-knockout mice (CRbL/L p130-/-) to determine it these proteins have a shared role in regulating cardiac myocyte cell cycle progression. Adult CRbL/L p130-/- mice demonstrated a threefold increase in the heart weight-to-body weight ratio and showed increased numbers of bromodeoxyuridine- and phosphorylated histone H3-positive nuclei, consistent with persistent myocyte cycling. Likewise, the combined deletion of Rb plus p130 up-regulated myocardial expression of Myc, E2F-1, and G1 cyclin-dependent kinase activities, synergistically. Thus, Rb and p130 have overlapping functional roles in vivo to suppress cell cycle activators, including Myc, and maintain quiescence in postnatal cardiac muscle.     

NDRG2: a Myc-repressed gene involved in cancer and cell stress

As a master switch for cell proliferation and differentiation, Myc exerts its biological functions mainly through transcrip-tional regulation of its target genes, which are involved in cells' interaction and communication with their external environment. The N-Myc downstream-regulated gene ( NDRG ) family is composed of NDRG1, NDRG2, NDRG3 and NDRG4 , which are important in cell proliferation and differentiation. This review summarizes the recent studies on the structure, tissue distribution and functions of NDRG2 that try to show its significance in studying cancer and its therapeutic potential.