Celio Pouponnot

TGF|[beta]| influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b

Transforming growth factor-β (TGFβ) is a cytokine that arrests epithelial cell division by switching off the proto-oncogene c-myc and rapidly switching on cyclin-dependent kinase (CDK) inhibitors such as p15INK4b. Gene responses to TGFβ involve Smad transcription factors that are directly activated by the TGFβ receptor. Why downregulation of c-myc expression by TGFβ is required for rapid activation of p15INK4b has remained unknown. Here we provide evidence that TGFβ signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFβ-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. Thus, two separate TGFβ-dependent inputs — Smad-mediated transactivation and relief of repression by Myc — keep tight control over p15INK4b activation.

Physical and Functional Interaction of SMADs and p300/CBP

SMADs are transforming growth factor β (TGF-β) receptor substrates and mediators of TGF-β transcriptional responses. Here we provide evidence that the coactivators p300 and CBP interact with Smads 1 through 4. The biological relevance of this interaction is shown in vivo by overexpression of the adenovirus E1A protein and mutant forms of E1A that lack p300-binding sites. Wild-type E1A, but not the mutants, inhibits SMAD-dependent transcriptional responses to TGF-β. E1A also inhibits the intrinsic transactivating function of the Smad4 MH2 domain. In addition, overexpression of p300 enhances SMAD-dependent transactivation. Our results suggest a role for p300/CBP in SMAD-mediated transcriptional activation and provide an explanation for the observed ability of E1A to interfere with TGF-β action.

PFKFB4 controls embryonic patterning via Akt signalling independently of glycolysis

How metabolism regulators play roles during early development remains elusive. Here we show that PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4), a glycolysis regulator, is critical for controlling dorsal ectoderm global patterning in gastrulating frog embryos via a non-glycolytic function. PFKFB4 is required for dorsal ectoderm progenitors to proceed towards more specified fates including neural and non-neural ectoderm, neural crest or placodes. This function is mediated by Akt signalling, a major pathway that integrates cell homeostasis and survival parameters. Restoring Akt signalling rescues the loss of PFKFB4 in vivo. In contrast, glycolysis is not essential for frog development at this stage. Our study reveals the existence of a PFKFB4-Akt checkpoint that links cell homeostasis to the ability of progenitor cells to undergo differentiation, and uncovers glycolysis-independent functions of PFKFB4.

MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian))

Review on MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)), with data on DNA, on the protein encoded, and where the gene is implicated.

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

NRAS-driven melanoma: A RAF can hide another

ABSTRACT Using mouse genetics, we recently showed that BRAF has a critical role in initiation of NRAS-driven melanoma that cannot be compensated by CRAF. In contrast, RAF proteins display compensatory functions in fully established tumors and ARAF can sustain proliferation in the absence of BRAF and CRAF, highlighting an addiction to RAF signaling in NRAS-driven melanoma.