Overexpression of CR/periphilin downregulates Cdc7 expression and induces S-phase arrest

Kurita, Megumi; Suzuki, Hiroaki; Masai, Hisao; Mizumoto, Kiyohisa; Ogata, Etsuro; Nishimoto, Ikuo; Aiso, Sadakazu; Matsuoka, Masao

doi:10.1016/j.bbrc.2004.09.083

Cited by 15 publications

(13 citation statements)

References 23 publications

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“…Other isoforms have been described to be involved in gastric cancer (Line et al, 2002) and cell-cycle regulation (Kurita et al, 2004(Kurita et al, , 2007. Beyond these facts, the physiological function of periphilin is only of a hypothetical nature.…”

Section: Discussionmentioning

confidence: 95%

“…It has been originally identified as interactor of periplakin, a precursor of the cornified cell envelope (Kazerounian and Aho, 2003). Interestingly, it is also known as gastric cancer-associated isoform GA50 (Line et al, 2002), and another isoform retards S-phase progression (Kurita et al, 2004). The functional diversity is in part ascribable to the fact that the human periphilin gene at chromosome 12q12 contains 14 exons, of which exons 2, 4, 7, and 11-14 are subject to alternative splicing in a tissue specific manner (Kazerounian and Aho, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…The gastric cancer-associated isoform GA50 is characterized by cryptic splicing within exon 11, which leads to the replacement of amino acids 350-374 by amino acids encoded by exons 12-14 (Line et al, 2002). The variant, which induces S-phase arrest when overexpressed, has a deletion of exon 7 (CR-D E7) and acts as a repressor of both mRNA and protein expression of Cdc7, a regulator of the initiation and continuation of DNA replication (Kurita et al, 2004). To this end, periphilin functionally interacts with the mSin3A/histone deacetylase 1 (HDAC1) co-repressor complex (Kurita et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Periphilin is strongly expressed in the murine nervous system and is indispensable for murine development

Soehn

Pham

Schaeferhoff

et al. 2009

Genesis

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Periphilin is involved in multiple processes in vivo. To explore its physiological role from an organismic perspective, we generated mice with a gene trap insertion in the periphilin-1 gene. Based on beta-gal reporter activity, a widespread periphilin expression was evident, especially in the developing somites and limbs, the embryonic nervous system, and the adult brain. In accordance with this broad expression, homozygous deficiency of periphilin was lethal in early embryogenesis. Mice with a heterozygous deficiency did not show any abnormalities of brain morphology and function, neither histologically nor regarding the transcriptome. Interestingly, the reduction of the periphilin-1 gene dosage was compensated by an increased expression of the remaining wild-type allele in the brain. These results point to an indispensable function of periphilin during murine development and an important role in the nervous system, reflected by a strong and tightly regulated expression in the murine brain.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Periphilin is strongly expressed in the murine nervous system and is indispensable for murine development

Soehn

Pham

Schaeferhoff

et al. 2009

Genesis

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“…In human cells, Dbf4 and Drf1 accumulate in S phase and regulate Cdc7 activity during the cell cycle, although the specific role of the two regulators has not yet been fully elucidated (15). Other proteins regulate formation of the complex at the transcriptional level; whereas Dbf4 is an E2F-regulated gene, Cdc7 gene expression is directly regulated by the transcription factor Myb (16) and is repressed by Cdc7 expression repressor (CR)/periphilin (17).…”

Section: Cell Division Cycle 7 Kinasementioning

confidence: 99%

Targeting Cell Division Cycle 7 Kinase: A New Approach for Cancer Therapy

Montagnoli

Moll

Colotta

2010

Clinical Cancer Research

105

107

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The cell division cycle 7 (Cdc7) is a serine-threonine kinase, originally discovered in budding yeast, required to initiate DNA replication. Human Cdc7 phosphorylates the minichromosome maintenance protein 2 (Mcm2), a component of the DNA replicative helicase needed for genome duplication. Inhibition of Cdc7 in cancer cells impairs progression through S phase, inducing a p53-independent apoptotic cell death, whereas in normal cells, it does not affect cell viability. Small molecule compounds able to interfere with Cdc7 activity have been identified and shown to be effective in controlling tumor growth in animal models. Two Cdc7 inhibitors are currently in phase I clinical development. Inhibition of Cdc7 kinase activity in cancer cells restricts DNA replication and induces apoptotic cell death by an unprecedented molecular mechanism of action.

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“…Since RTP801/REDD1 overexpression was shown to abolish keratinocyte differentiation (Ellisen et al, 2002) and also contributed to PI3K-dependent malignant growth of prostate cancer cells (Schwarzer et al, 2005), its upregulation after PI3K activation may be important for the preservation of the proliferationcompetent state of keratinocytes as observed in the 4-OHT-treated organotypic cultures. The concomittant downregulation of periphilin1 and of other differentiationinducing genes may enhance this effect, and this may be further enforced by enhancement of cell-cycle progression, since periphilin1 acts as a repressor of Cdc7 expression and induces S-phase arrest (Kazerounian and Aho, 2003;Kurita et al, 2004).…”

Section: Pi3k Activation Delays Keratinocyte Differentiationmentioning

confidence: 99%

Regulation of epidermal homeostasis and repair by phosphoinositide 3-kinase

Pankow

Bamberger

Klippel

et al. 2006

Journal of Cell Science

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The epidermis undergoes continuous self-renewal to maintain its protective function. Whereas growth factors are known to modulate overall skin homeostasis, the intracellular signaling pathways, which control the delicate balance between proliferation and differentiation in keratinocytes, are largely unknown. Here we show transient upregulation of the phosphoinositide 3-kinase (PI3K) catalytic subunits p110α and p110β in differentiating keratinocytes in vitro, expression of these subunits in the epidermis of normal and wounded skin, and enhanced Akt phosphorylation in the hyperproliferative wound epidermis. Stimulation of PI3K activity in cultured keratinocytes by stable expression of an inducible, constitutively active PI3K mutant promoted cell proliferation and inhibited terminal differentiation in keratinocyte monocultures and induced the formation of a hyperplastic, disorganized and poorly differentiated epithelium in organotypic skin cultures. Activation of PI3K signaling also caused reorganization of the actin cytoskeleton and induced keratinocyte migration in vitro and in skin organ cultures. The identification of 122 genes, which are differentially expressed after induction of PI3K signaling provides insight into the molecular mechanisms underlying the observed effects of active PI3K on keratinocytes and indicates that hyperproliferation may be achieved at the expense of genome integrity. These results identify PI3K as an important intracellular regulator of epidermal homeostasis and repair.

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Overexpression of CR/periphilin downregulates Cdc7 expression and induces S-phase arrest

Cited by 15 publications

References 23 publications

Periphilin is strongly expressed in the murine nervous system and is indispensable for murine development

Periphilin is strongly expressed in the murine nervous system and is indispensable for murine development

Targeting Cell Division Cycle 7 Kinase: A New Approach for Cancer Therapy

Regulation of epidermal homeostasis and repair by phosphoinositide 3-kinase

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