Disease relevance of CENPF

• Nonrandom chromosomal imbalances in esophageal squamous cell carcinoma cell lines: possible involvement of the ATF3 and CENPF genes in the 1q32 amplicon [1].
• The protein, which we have named "mitosin," was identified by direct binding to purified retinoblastoma protein in vitro with a region distantly related to the retinoblastoma protein-binding site of E2F-1 [2].
• The expression of mitosin, a novel proliferation-associated molecule was evaluated immunohistochemically in a consecutive series of 47 patients with primary intracranial benign and atypical meningiomas [3].
• AH antigen, initially defined by an antibody present in a melanoma patient, is a cell surface antigen found on approximately 65% of melanoma cell lines [4].
• Mitosin (a new proliferation marker) correlates with clinical outcome in node-negative breast cancer [5].

High impact information on CENPF

• It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation [6].
• Centromere protein F (CENP-F) (or mitosin) accumulates to become an abundant nuclear protein in G2, assembles at kinetochores in late G2, remains kinetochore-bound until anaphase, and is degraded at the end of mitosis [7].
• Centromere protein-F (CENP-F) is mammalian kinetochore protein that was recently identified by an autoimmune serum (Rattner, J. B., A. Rao, M. J. Fritzler, D. W. Valencia, and T. J. Yen. Cell Motil. Cytoskeleton. 26:214-226) [8].
• These phenotypes collectively imply defects in motor functions in mitosin-depleted cells and are similar to those of CENP-E depletion [9].
• Mitosin (also named CENP-F) is a large human nuclear protein transiently associated with the outer kinetochore plate in M phase [9].

Biological context of CENPF

• CENPE and CENPF are human kinetochore proteins of 312 and approximately 400 kDa, respectively [10].
• Chromosomal localization of the genes encoding the kinetochore proteins CENPE and CENPF to human chromosomes 4q24-->q25 and 1q32-->q41, respectively, by fluorescence in situ hybridization [10].
• In addition, after being arrested in pseudometaphase for approximately 2 h, mitosin-depleted cells died before anaphase initiation through apoptosis [9].
• These findings suggest mitosin to be a negative regulator of ATF4 in interphase through direct interaction [11].
• Moreover, overexpression of full-length mitosin repressed the transactivation activity of ATF4 in dual luciferase-based reporter assays, while knocking down mitosin expression manifested the opposite effects [11].

Anatomical context of CENPF

• Using RNA interference and fluorescence microscopy, we showed that mitosin depletion attenuated chromosome congression and led to metaphase arrest with misaligned polar chromosomes whose kinetochores showed few cold-stable microtubules [9].
• Mitosin/CENP-F is a human nuclear matrix protein with multiple leucine zipper motifs [11].
• We showed that mitosin molecules entering nuclei after nuclear envelope breakdown (NEBD) were not assembled onto kinetochores efficiently, suggesting that the mitosin-kinetochore interaction is stabilized prior to NEBD [12].
• Mitosin is a novel 350-kDa nuclear phosphoprotein that dramatically relocates from the evenly nuclear distribution in S phase to the centromere/kinetochore and mitotic apparatus in M phase [13].

Associations of CENPF with chemical compounds

• Studies of the centromere-associated protein mitosin revealed that treatment with lovastatin and paclitaxel resulted in increased mitosin levels and that lovastatin altered the association of mitosin with condensed chromosomes [14].
• Using a new monoclonal antibody (14C10), this pilot study evaluated mitosin expression by IHC in a series of 386 node-negative, formalin-fixed, archival breast cancers and correlated the results with several prognostic factors and clinical outcome (median follow-up, 78 months; range 3-214 months) [5].

Physical interactions of CENPF

• The C-terminal portion of mitosin between residues 2488 and 3113 bound to ATF4 through two distinct domains, one of which was a leucine zipper motif [11].

Other interactions of CENPF

• The CENPF gene, which encodes a structural protein of the kinetochore, maps to chromosome 1q32-->q41 within close proximity to the genetic locus that is linked to Van der Woude syndrome [10].
• The higher proliferation indices were obtained with mitosin and PCNA and the lower ones with TopoIIalpha [3].
• In multivariate analysis, the labeling indices of mitosin (p = 0.035) and Ki-67 (p = 0.032), along with tumor size, were shown to provide independent prognostic information, beyond that obtained by standard clinical and pathological parameters [3].
• Mitosin/CENP-F is a large nuclear/kinetochore protein containing multiple leucine zipper motifs potentially for protein interactions [15].
• Nuclear grade, mitotic activity, and biomarker profile (Her2-neu and mitosin expression patterns) in pretreatment tumors were correlated with the postchemotherapy pathologic response [16].

Analytical, diagnostic and therapeutic context of CENPF

• Univariate analysis disclosed mitosin LI (p = 0.033) along with the mitotic index (p = 0.024) and tumor size (p = 0.028) as significant predictors of shortened recurrence-free survival [3].
• However, in a univariate cutpoint analysis of disease-free survival (DFS), patients with high levels of mitosin (>9% positive cells) had significantly worse DFS than did patients with lower levels (68% versus 84% at 5 years, respectively) [5].
• Mitosin also was correlated significantly with CPR and NCR (P = 0.028) [16].
• CONCLUSIONS: The current results indicate that tumor nuclear grade and tumor proliferative activity (mitotic activity and mitosin immunostaining) of pretreatment tumors in patients with breast carcinoma may serve as important indicators for the pathologic responsiveness of tumors to neoadjuvant, anthracycline-based chemotherapy [16].

References