Differential regulation of transcription and induction of programmed cell death by human p53‐family members p63 and p73

Dietz, Sebastian; Rother, Karen; Bamberger, Casimir; Schmale, Hartwig; Mössner, Joachim; Engeland, Kurt

doi:10.1016/s0014-5793(02)03093-4

Cited by 56 publications

(82 citation statements)

References 39 publications

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“…As controls and consistent with previous observations mRNA levels for known p53 target genes like p21 WAF1/CIP1 and mdm2 were found to be upregulated and previously described targets like cyclin A, Cyclin B, cdk1 and cdc25C were downregulated [25]. Furthermore, under the experimental conditions employed changes in expression of p53 target genes precede the changes due to impending apoptosis [17]. Following the microarray analysis as an indicator, we confirmed the p53-dependent decrease of the Cks2 mRNA levels by real-time RT-PCR quantification in two independent experiments yielding an average of 10.1-fold downregulation of Cks2 mRNA.…”

Section: Resultssupporting

confidence: 90%

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Gene expression of cyclin‐dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73

Rother¹,

Dengl²,

Lorenz³

et al. 2007

FEBS Letters

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Cks2 proteins are essential components of cyclin/cyclin-dependent kinase complexes and contribute to cell cycle control. We identify Cks2 as a transcriptional target downregulated by the tumor suppressor p53. Cks2 expression was found to be repressed by p53 both at the mRNA and the protein levels. p53 downregulates transcription from the Cks2 promoter in a dosedependent manner and in all cell types tested. This repression appears to be independent of p53 binding to the Cks2 promoter. In contrast to p53, neither p63 nor p73 proteins can repress Cks2 transcription. Thus p53, rather than its homologues p63 and p73, may contribute to control of the first metaphase/anaphase transition of mammalian meiosis by downregulation of Cks2 expression.

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Section: Resultssupporting

confidence: 90%

“…3B). Moreover, we had found p73a, p73b, TAp63c and TA * p63c able to activate transcription from a p21 WAF1/CIP1 reporter [9,17]. This confirms them to be transcriptionally active but unable to alter expression from the Cks2 promoter.…”

Section: Expression Of P73 or P63 Proteins Does Not Altersupporting

confidence: 56%

Gene expression of cyclin‐dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73

Rother¹,

Dengl²,

Lorenz³

et al. 2007

FEBS Letters

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“…Regulatory pathways that involve isoforms of the p53 family members p63 and p73 may be involved. The latter regulate Waf1 mRNA expression (Dietz et al, 2002), and their participation may explain the partial p53 dependence in the observed DPI-induced G 1 checkpoint (Figure 6b). Regardless, our data show that ATM is as responsive to change in the cellular redox environment as it is to DNA damage.…”

Section: Discussionmentioning

confidence: 97%

Regulation of normal cell cycle progression by flavin-containing oxidases

Prakash¹,

Toledo²,

Pandey³

et al. 2007

Oncogene

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Mechanisms underlying the role of reactive oxygen species (ROS) generated by flavin-containing oxidases in regulating cell cycle progression were examined in human and rodent fibroblasts. Incubation of confluent cell cultures with nontoxic/nonclastogenic concentrations of the flavoprotein inhibitor, diphenyleneiodonium (DPI), reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity and basal ROS levels, but increased proteolysis of cyclin D1, p21 Waf1 and phospho-p38 MAPK . When these cells were allowed to proliferate by subculture in DPI-free medium, an extensive G 1 delay was observed with concomitant activation of p53/p21 Waf1 signaling and reduced phosphorylation of mitogen-activated kinases. Compensation for decreased oxidant generation by simultaneous exposure to DPI and nontoxic doses of the ROS generators, c-radiation or t-butyl-hydroperoxide, attenuated the G 1 delay. Whereas the DPI-induced G 1 checkpoint was completely dependent on PHOX91, ATM and WAF1, it was only partially dependent on P53. Interestingly, G 1 to S progression was not affected when another flavin-containing enzyme, nitric oxide synthase, was inhibited nor was it associated with changes in mitochondrial membrane potential. Proliferating cells treated with DPI also experienced a significant but attenuated delay in G 2 . We propose that ATM performs a critical function in mediating normal cellular proliferation that is regulated by nonphagocytic NAD(P)H oxidase enzymes activity, which may serve as a novel target for arresting cancer cells in G 1 .

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“…A potential mechanism regulating this process might be through p63, which has been shown to activate transcription of p21. 5,6 Further, p63 is also known to induce expression of Jagged1 7 which is involved in Notch signaling and osteoclastogenesis. 8 p63 is a member of the gene family that includes p53 and p73.…”

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confidence: 99%

Giant cell tumor of bone express p63

Dickson

Wunder

et al. 2008

Modern Pathology

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p63 contributes to skeletal development and tumor formation; however, little is known regarding its activity in the context of bone and soft tissue neoplasms. The purpose of this study was to investigate p63 expression in giant cell tumor of bone and to determine whether it can be used to discriminate between other giant cell-rich tumors. Seventeen cases of giant cell tumor of bone were examined to determine the cell type expressing p63 and identify the isoforms present. Total RNA or cell protein was extracted from mononuclear-or giant cellenriched fractions or intact giant cell tumor of bone and examined by RT-PCR or western blot, respectively. Immunohistochemistry was used to evaluate p63 expression in paraffin embedded sections of giant cell tumor of bone and in tumors containing multinucleated giant cells, including: giant cell tumor of tendon sheath, pigmented villonodular synovitis, aneurysmal bone cyst, chondroblastoma, and central giant cell granuloma. The mononuclear cell component in all cases of giant cell tumor of bone was found to express all forms of TAp63 (a, b, and c), whereas only low levels of the TAp63 a and b isoforms were detected in multinucleated cells; DNp63 was not detected in these tumors. Western blot analysis identified p63 protein as being predominately localized to mononuclear cells compared to giant cells. This was confirmed by immunohistochemical staining of paraffin-embedded tumor sections, with expression identified in all cases of giant cell tumor of bone. Only a proportion of cases of aneurysmal bone cyst and chondroblastoma showed p63 immunoreactivity whereas it was not detected in central giant cell granuloma, giant cell tumor of tendon sheath, or pigmented villonodular synovitis. The differential expression of p63 in giant cell tumor of bone and central giant cell granuloma suggest that these two tumors may have a different pathogenesis. Moreover, p63 may be a useful biomarker to differentiate giant cell tumor of bone from central giant cell granuloma and other giant cell-rich tumors, such as giant cell tumor of tendon sheath and pigmented villonodular synovitis.

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Differential regulation of transcription and induction of programmed cell death by human p53‐family members p63 and p73

Cited by 56 publications

References 39 publications

Gene expression of cyclin‐dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73

Gene expression of cyclin‐dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73

Regulation of normal cell cycle progression by flavin-containing oxidases

Giant cell tumor of bone express p63

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