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Pier Paolo Pandolfi

Publications and source records attributed to Pier Paolo Pandolfi.

98 records · Page 6Linked to original sources
PubMed2002

SUMO-1 protease-1 regulates gene transcription through PML.

During a screen to identify c-Jun activators, we isolated a cysteine protease, SuPr-1, that induced c-Jun-dependent transcription independently of c-Jun phosphorylation. SuPr-1 is a member of a new family of proteases that hydrolyze the ubiquitin-like modifier, SUMO-1. SuPr-1 hydrolyzed SUMO-1-modified forms of the promyelocytic leukemia gene product, PML, and altered the subcellular distribution of PML in nuclear PODs (PML oncogenic domains). SuPr-1 also altered the distribution of other nuclear POD-associated proteins, such as CBP and Daxx, that act as transcriptional regulators. SuPr-1 action on transcription was enhanced by PML, and SuPr-1 failed to activate transcription in PML-deficient fibroblasts. Our studies establish an important role for SUMO proteases in transcription.

Amino Acid Sequence↗
PubMed2002

Reciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders?

Chromosomal translocations are frequently involved in the pathogenesis of leukemias, lymphomas and sarcomas. They can lead to aberrant expression of oncogenes or the generation of chimeric proteins. Classically, one of the products is thought to be oncogenic. For example, in acute promyelocytic leukaemia (APL), reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) gene lead to the formation of two fusion genes: X-RARalpha and RARalpha-X (where X is the alternative RARalpha fusion partner: PML, PLZF, NPM, NuMA and STAT 5b). The X-RARalpha fusion protein is indeed oncogenic. However, recent data indicate that the RARalpha-X product is also critical in determining the biological features of this leukemia. Here, we review the current knowledge on the role of reciprocal products in cancer pathogenesis, and highlight how their expression might impact on the biology of their respective tumour types.

Animals↗
PubMed2002

Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling.

The molecular mechanisms that regulate coordinated and colinear activation of Hox gene expression in space and time remain poorly understood. Here we demonstrate that Plzf regulates the spatial expression of the AbdB HoxD gene complex by binding to regulatory elements required for restricted Hox gene expression and can recruit histone deacetylases to these sites. We show by scanning forced microscopy that Plzf, via homodimerization, can form DNA loops and bridge distant Plzf binding sites located within HoxD gene regulatory elements. Furthermore, we demonstrate that Plzf physically interacts with Polycomb proteins on DNA. We propose a model by which the balance between activating morphogenic signals and transcriptional repressors such as Plzf establishes proper Hox gene expression boundaries in the limb bud.

Animals↗
PubMed2002

Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation.

We have inactivated pRb, p107, and p130 in astrocytes by transgenic expression of T(121) (a truncated SV40 T antigen) under the GFAP promoter. Founder mice died perinatally with extensive expansion of neural precursor and anaplastic astrocyte populations. In astrocytes, aberrant proliferation and extensive apoptosis were induced. Using a conditional allele of T(121), early lethality was circumvented, and adult mice developed high-grade astrocytoma, in which regions of decreased apoptosis expressed activated Akt. Indeed, astrocytoma development was accelerated in a PTEN(+/-), but not p53(+/-), background. These studies establish a highly penetrant preclinical model for astrocytoma based on events observed in the human disease and further provide insight into the role of PTEN mutation in astrocytoma progression.

Aging↗
PubMed2002

PTEN and TNF-alpha regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-kappaB-dependent pathway.

BACKGROUND & AIMS: PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a dual-specificity phosphatase implicated in embryonic development, intestinal cell proliferation and differentiation, and tumor suppression. The transcription factor Cdx-2 is critical in intestinal development and homeostasis, and its expression is altered in colorectal cancers. However, the regulation of the Cdx-2 gene has not been entirely elucidated. Here, we hypothesize that Cdx-2 may be a target of PTEN signaling in the intestine. METHODS: The expression patterns for Cdx-2 and PTEN along wild-type mouse colon, as well as in colon tumors occurring in Pten(+/-) mice, were examined. The effect of PTEN or phosphatidylinositol 3-kinase inhibition and tumor necrosis factor alpha on Cdx-2 messenger RNA and protein expression, Cdx-2 DNA binding activity, and the promoter activity of the Cdx-2 gene was analyzed in human colon cancer cell lines. RESULTS: Cdx-2 expression correlates with PTEN along the length of the murine colon and in colonic polyps that develop in Pten(+/-) mice. In colon cancer cells, PTEN stimulates Cdx-2 protein expression and the transcriptional activity of the Cdx-2 promoter. Phosphatidylinositol 3-kinase inhibition by wortmannin or by a dominant-negative phosphatidylinositol 3-kinase mimics the Cdx-2 stimulation by PTEN. Inversely, cell treatment by tumor necrosis factor alpha decreases Cdx-2 expression. Phosphatidylinositol 3-kinase inhibition by PTEN or wortmannin has an inverse effect compared with tumor necrosis factor alpha on the balance between the p50 and p65 subunits of nuclear factor kappaB. p65 inhibits the activity of the Cdx-2 promoter, whereas p50 prevents p65 action. CONCLUSIONS: Our results suggest that the intestinal Cdx-2 homeobox gene is a target of PTEN/phosphatidylinositol 3-kinase signaling and tumor necrosis factor alpha signaling via nuclear factor kappaB-dependent pathways.

Androstadienes↗
PubMed2002

Designed transcription factors as structural, functional and therapeutic probes of chromatin in vivo. Fourth in review series on chromatin dynamics.

Despite its central importance in gene regulation, chromatin in mammalian cells remains relatively poorly understood-a predicament due to the paucity of robust genetic tools in mammals, the complexity of the chromatin remodeling machinery, and the dynamic properties of chromatin in vivo. Here we review recent developments in understanding endogenous mammalian gene regulation via the use of designed transcription factors (TFs). These include mutated forms of naturally occurring TFs that exhibit dominant-negative activity, and designed proteins with novel, predetermined DNA-binding specificities. Systematic targeting of designed TFs to particular promoters is helping to illuminate the complex rules that chromatin imposes on TF access and action in vivo. We evaluate the potential applications of these proteins as probes of mammalian chromatin-based regulatory pathways and their potential for the therapy of human disease, highlighting leukemia in particular.

Animals↗
PubMed2002

Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage.

Activation of Akt, or protein kinase B, is frequently observed in human cancers. Here we report that Akt activation via overexpression of a constitutively active form or via the loss of PTEN can overcome a G(2)/M cell cycle checkpoint that is induced by DNA damage. Activated Akt also alleviates the reduction in CDC2 activity and mitotic index upon exposure to DNA damage. In addition, we found that PTEN null embryonic stem (ES) cells transit faster from the G(2)/M to the G(1) phase of the cell cycle when compared to wild-type ES cells and that inhibition of phosphoinositol-3-kinase (PI3K) in HEK293 cells elicits G(2) arrest that is alleviated by activated Akt. Furthermore, the transition from the G(2)/M to the G(1) phase of the cell cycle in Akt1 null mouse embryo fibroblasts (MEFs) is attenuated when compared to that of wild-type MEFs. These results indicate that the PI3K/PTEN/Akt pathway plays a role in the regulation of G(2)/M transition. Thus, cells expressing activated Akt continue to divide, without being eliminated by apoptosis, in the presence of continuous exposure to mutagen and accumulate mutations, as measured by inactivation of an exogenously expressed herpes simplex virus thymidine kinase (HSV-tk) gene. This phenotype is independent of p53 status and cannot be reproduced by overexpression of Bcl-2 or Myc and Bcl-2 but seems to counteract a cell cycle checkpoint mediated by DNA mismatch repair (MMR). Accordingly, restoration of the G(2)/M cell cycle checkpoint and apoptosis in MMR-deficient cells, through reintroduction of the missing component of MMR, is alleviated by activated Akt. We suggest that this new activity of Akt in conjunction with its antiapoptotic activity may contribute to genetic instability and could explain its frequent activation in human cancers.

Animals↗