Expression of prohibitin 3? untranslated region suppressor RNA alters morphology and inhibits motility of breast cancer cells

Manjeshwar, Sharmila; Lerner, Megan R.; Zang, Xiaoping; Branam, Dannielle E.; Pento, J. Thomas; Lane, Mary M.; Lightfoot, Stan; Brackett, Daniel J.; Jupe, Eldon R.

doi:10.1007/s10735-004-2185-7

Cited by 20 publications

(21 citation statements)

References 29 publications

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“…When microinjected into normal human fibroblasts, Phb1 mRNA attenuated DNA synthesis, however, this effect was subsequently shown to be mediated by the 3Ј-untranslated region rather than the coding region of the cDNA (52,53). The mechanism of cell cycle regulation was determined by Wang et al (54,55) who showed Phb1 could bind Rb as well as E2F1 to repress their transcriptional activity (56).…”

Section: Discussionmentioning

confidence: 99%

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

Ross

Nagy

Kirken

2008

Journal of Biological Chemistry

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Many immune pathologies are the result of aberrant regulation of T lymphocytes. A functional proteomics approach utilizing two-dimensional gel electrophoresis coupled with mass spectrometry was employed to identify differentially expressed proteins in response to T cell activation. Two members of the prohibitin family of proteins, Phb1 and Phb2, were determined to be up-regulated 4 -5-fold upon activation of primary human T cells. Furthermore, their expression was dependent upon CD3 and CD28 signaling pathways that synergistically led to the upregulation (13-15-fold) of Phb1 and Phb2 mRNA levels as early as 48 h after activation. Additionally, orthophosphate labeling coupled with phosphoamino acid analysis identified Phb1 to be serine and Phb2 serine and tyrosine phosphorylated. Tyrosine phosphorylation of Phb2 was mapped to Tyr 248 using mass spectrometry and confirmed by mutagenesis and phosphospecific antibodies. In contrast to previous reports of Phb1 and Phb2 being nuclear localized, subcellular fractionation, immunofluorescent, and electron microscopy revealed both proteins to localize to the mitochondrial inner membrane of human T cells. Accordingly, small interfering RNA-mediated knockdown of Phbs in Kit225 cells resulted in disruption of mitochondrial membrane potential. Additionally, Phb1 and Phb2 protein levels were up-regulated 2.5-fold during cytokine deprivation-mediated apoptosis of Kit225 cells, suggesting this complex plays a protective role in human T cells. Taken together, Phb1 and Phb2 are novel phosphoproteins up-regulated during T cell activation that function to maintain mitochondrial integrity and thus represent previously unrecognized therapeutic targets for regulating T cell activation, differentiation, viability, and function.

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Section: Discussionmentioning

confidence: 99%

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

Ross

Nagy

Kirken

2008

Journal of Biological Chemistry

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“…The novel del T poly (T)8 alteration identified in this study is located in the 3 0 end of the CDK2-AP1 gene. Previous literature suggests the 3 0 end of gene sequences play a crucial role in RNA stability and splicing (Irmer and Clayton, 2001;Manjeshwar et al, 2003;Yasuda et al, 2003). In order to understand the relationship of the presence of this alteration to MMR function, we employed an in vitro human recombinant system to modulate hMLH1 expression.…”

Section: Discussionmentioning

confidence: 99%

Modulation of CDK2-AP1 (p12DOC−1) expression in human colorectal cancer

et al. 2005

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We have previously demonstrated an association between microsatellite instability and decreased CDK2-AP1 (p12 DOCÀ1 ) expression in human colorectal cancer (CRC) cell lines. In those same studies, induction of CDK2-AP1 expression promoted both cell cycle arrest and apoptosis. The goals of our present study were to better understand the mechanisms leading to reduced CDK2-AP1 expression in microsatellite unstable (MSI) CRC and to study further the effect of CDK2-AP1 modulation on cell proliferation and apoptosis utilizing RNA interference (RNAi) techniques. We used direct sequencing to screen for mutations of the poly (T)8 microsatellite-like region in the 3 0 end of the CDK2-AP1 gene in 24 CRC cell lines. We then utilized an in vitro human mismatch repair (MMR) recombinant system to assess for correction of the mutation and changes in CDK2-AP1 expression secondary to hMLH1 transfection. We also investigated the effect of CDK2-AP1 modulation in four settings: (1) native CDK2-AP1 absence, (2) endogenous CDK2-AP1 expression, (3) RNAi-induced CDK2-AP1 inhibition and (4) induced CDK2-AP1 over expression. The mutation -del T poly (T)8 -at the 3 0 end of the CDK2-AP1 gene was found in 3/12 (25%) of MSI CRC cell lines, but in none of the microsatellite stable samples (0/12). Interestingly, when wild-type MMR protein -MLH1 -was induced in an in vitro human recombinant system, the del T poly (T)8 mutation was reversed and CDK2-AP1 expression increased. RNAi-mediated CDK2-AP1 inhibition was associated with decreased apoptosis and increased cell proliferation in CDK2-AP1-non deficient CRC cell lines. We conclude that mutations in the microsatellite-like sequence of the CDK2-AP1 gene in MSI CRC are associated with decreased CDK2-AP1 expression. In addition, modulation of CDK2-AP1 expression in human CRC alters cell proliferation and apoptosis.

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“…12 Previous research suggested a functional role for this variant as the 3 0 UTR of this gene has been shown to have a regulatory function by blocking cell-cycle progression. 13 This same association was not observed with in follow-up studies of Australian women with breast cancer 14 or ovarian cancer. 15 In our report, the variant T allele was observed in five out of 64 alleles (7.8%), Abbreviation: Nr, not previously reported.…”

Section: Discussionmentioning

confidence: 60%

“…[13][14][15] Additional studies using a case-control design should be carried out explore the potential association between the functionally important T allele and prostate cancer susceptibility. Prohibitin has been speculated to have several different roles in the cell based on subcellular localization.…”

Section: Discussionmentioning

confidence: 99%

Prohibitin mutations are uncommon in prostate cancer families linked to chromosome 17q

White

Lange

Ray

et al. 2006

Prostate Cancer Prostatic Dis

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Background: Linkage studies have provided evidence for a prostate cancer susceptibility locus on chromosome 17q. The mitochondrial protein prohibitin (PHB) is a plausible candidate gene based on its chromosomal location (17q21) and known function. Methods: All coding regions and intron/exon junctions of the PHB gene were sequenced in 32 men from families participating in the University of Michigan Prostate Cancer Genetics Project that demonstrated evidence of linkage to 17q markers. Results: Although a number of nucleotide variants were identified, no coding region substitutions were identified in any of the 32 men with prostate cancer from 32 unrelated multiplex prostate cancer families. Conclusions: PHB mutations do not appear to account for the linkage signal on 17q21-22 detected in PCGP families. Fine mapping of this region is in progress to refine the candidate region and highlight additional candidate prostate cancer susceptibility genes for sequence analysis.

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Expression of prohibitin 3? untranslated region suppressor RNA alters morphology and inhibits motility of breast cancer cells

Cited by 20 publications

References 29 publications

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

Modulation of CDK2-AP1 (p12DOC−1) expression in human colorectal cancer

Prohibitin mutations are uncommon in prostate cancer families linked to chromosome 17q

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