PCNT
Identifiers
AliasesPCNT, KEN, MOPD2, PCN, PCNT2, PCNTB, PCTN2, SCKL4, pericentrin
External IDsOMIM: 605925 HomoloGene: 86942 GeneCards: PCNT
Orthologs
SpeciesHumanMouse
Entrez

5116

n/a

Ensembl

ENSG00000160299

n/a

UniProt

O95613

n/a

RefSeq (mRNA)

NM_006031
NM_001315529

n/a

RefSeq (protein)

NP_001302458
NP_006022

n/a

Location (UCSC)Chr 21: 46.32 – 46.45 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Pericentrin (kendrin), also known as PCNT and pericentrin-B (PCNTB), is a protein which in humans is encoded by the PCNT gene on chromosome 21.[3][4][5][6] This protein localizes to the centrosome and recruits proteins to the pericentriolar matrix (PCM) to ensure proper centrosome and mitotic spindle formation, and thus, uninterrupted cell cycle progression.[3][7][8][9][10] This gene is implicated in many diseases and disorders, including congenital disorders such as microcephalic osteodysplastic primordial dwarfism type II (MOPDII) and Seckel syndrome.[7][8]

Structure

PCNT is a 360 kDa protein which contains a series of coiled coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus.[3][6][7][8][9][11][12] The PACT domain is responsible for targeting the protein to the centrosomes and attaching it to the centriole walls during interphase.[7][8] In addition, PCNT possesses five nuclear export sequences which all contribute to its nuclear export into the cytoplasm, as well as one nuclear localization signal composed of three clusters of basic amino acids, all of which contribute to the protein's nuclear localization.[7]

PCNTB, a cDNA homolog of PCNT, was identified and described by Li et al. to share a sequence identity of 61% and similarity of 75%. However, compared to PCNT, PCNTB contains an additional coiled coil domain and unique 1000-residue C-terminus, suggesting that these two may be separate proteins in a new CPM superfamily.[6] As with PCNT, the C-terminus of PCNTB contains functional domains for centriole localization and CEP215 binding. The N-terminus may also contain a functional domain that associates with the C-terminus domain, and this association is required for engagement with the centriole.[13]

Function

The protein encoded by this gene is expressed in the cytoplasm and centrosome throughout the cell cycle, and to a lesser extent, in the nucleus. It is an integral component of the PCM, which is a centrosome scaffold that anchors microtubule nucleating complexes and other centrosomal proteins.[3][6][7][9][13][14] In one model, PCNT complexes with CEP215 and is phosphorylated by PLK1, leading to PCM component recruitment and organization, centrosome maturation, and spindle formation.[8][13] The protein controls the nucleation of microtubules by interacting with the microtubule nucleation component γ-tubulin, thus anchoring the γ-tubulin ring complex to the centrosome, which is essential for bipolar spindle formation and chromosome assembly in early mitosis.[3][7][8][9][10] This ensures normal function and organization of the centrosomes, mitotic spindles, and cytoskeleton, and by extension, regulation over cell cycle progression and checkpoints.[3][7][8][9][14] Downregulation of PCNT disrupted mitotic checkpoints and arrested the cell at the G2/M checkpoint, leading to cell death.[12][14] Moreover, microtubule functioning was also disrupted, resulting in mono- or multipolar spindles, chromosomal misalignment, premature sister chromatid separation, and aneuploidy.[8][14]

PCNT is highly abundant in skeletal muscle, indicating that it may be involved in muscle insulin action.[9] PCNT is also involved in neuronal development through its interaction with DISC1 to regulate microtubule organization.[10]

Clinical significance

Mutations in the PCNT gene have been linked to Down syndrome (DS); two types of primordial dwarfism, MOPDII and Seckel syndrome; intrauterine growth retardation; cardiomyopathy; early onset type 2 diabetes; chronic myeloid leukemia (CML); bipolar affective disorder; and other congenital disorders.[7][8][10][12][13][14] In particular, the short stature and small brain size characteristic of MOPDII and Seckel syndrome have been attributed to centrosome dysfunction and cell growth disruption as a result of PCNT malfunction.[7] Additionally, premature aging, cerebral involution, inflammatory and immune responses are linked to DS associated with PCNT mutations, while severe insulin resistance, diabetes, and dyslipidemia are featured in MOPDII associated with PCNT mutations.[9][12]

Interactions

PCNT has been shown to interact with:

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000160299 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 3 4 5 6 7 "Entrez Gene: PCNT pericentrin (kendrin)".
  4. ↑ Chen H, Gos A, Morris MA, Antonarakis SE (Aug 1996). "Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter". Genomics. 35 (3): 620–4. doi:10.1006/geno.1996.0411. PMID 8812505.
  5. ↑ Flory MR, Moser MJ, Monnat RJ, Davis TN (May 2000). "Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 5919–23. Bibcode:2000PNAS...97.5919F. doi:10.1073/pnas.97.11.5919. PMC 18534. PMID 10823944.
  6. 1 2 3 4 5 Li Q, Hansen D, Killilea A, Joshi HC, Palazzo RE, Balczon R (Feb 2001). "Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1". Journal of Cell Science. 114 (Pt 4): 797–809. doi:10.1242/jcs.114.4.797. PMID 11171385.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Liu Q, Yu J, Zhuo X, Jiang Q, Zhang C (Aug 2010). "Pericentrin contains five NESs and an NLS essential for its nucleocytoplasmic trafficking during the cell cycle". Cell Research. 20 (8): 948–62. doi:10.1038/cr.2010.89. PMID 20567258.
  8. 1 2 3 4 5 6 7 8 9 10 Kim S, Rhee K (2014). "Importance of the CEP215-pericentrin interaction for centrosome maturation during mitosis". PLOS ONE. 9 (1): e87016. Bibcode:2014PLoSO...987016K. doi:10.1371/journal.pone.0087016. PMC 3899370. PMID 24466316.
  9. 1 2 3 4 5 6 7 Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YC, Szekeres F, Krook A, Nolan JJ, O'Driscoll M, Bober M, O'Rahilly S, Jackson AP, Semple RK (Mar 2011). "Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes". Diabetes. 60 (3): 925–35. doi:10.2337/db10-1334. PMC 3046854. PMID 21270239.
  10. 1 2 3 4 Shimizu S, Matsuzaki S, Hattori T, Kumamoto N, Miyoshi K, Katayama T, Tohyama M (Dec 2008). "DISC1-kendrin interaction is involved in centrosomal microtubule network formation". Biochemical and Biophysical Research Communications. 377 (4): 1051–6. doi:10.1016/j.bbrc.2008.10.100. PMID 18955030.
  11. ↑ Gillingham AK, Munro S (Dec 2000). "The PACT domain, a conserved centrosomal targeting motif in the coiled-coil proteins AKAP450 and pericentrin". EMBO Reports. 1 (6): 524–9. doi:10.1093/embo-reports/kvd105. PMC 1083777. PMID 11263498.
  12. 1 2 3 4 Salemi M, Barone C, Romano C, Salluzzo R, Caraci F, Cantarella RA, Salluzzo MG, Drago F, Romano C, Bosco P (Nov 2013). "Pericentrin expression in Down's syndrome". Neurological Sciences. 34 (11): 2023–5. doi:10.1007/s10072-013-1529-z. PMID 23979692. S2CID 1823570.
  13. 1 2 3 4 5 Lee K, Rhee K (Jul 2012). "Separase-dependent cleavage of pericentrin B is necessary and sufficient for centriole disengagement during mitosis". Cell Cycle. 11 (13): 2476–85. doi:10.4161/cc.20878. PMID 22722493.
  14. 1 2 3 4 5 Unal S, Alanay Y, Cetin M, Boduroglu K, Utine E, Cormier-Daire V, Huber C, Ozsurekci Y, Kilic E, Simsek Kiper OP, Gumruk F (Feb 2014). "Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): a potential role of pericentrin in hematopoiesis". Pediatric Blood & Cancer. 61 (2): 302–5. doi:10.1002/pbc.24783. PMID 24106199. S2CID 13192693.

Further reading

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