PINX1

PIN2/TERF1 interacting, telomerase inhibitor 1
Identifiers
Symbols PINX1 ; LPTL; LPTS
External IDs OMIM: 606505 MGI: 1919650 HomoloGene: 134540 GeneCards: PINX1 Gene
Orthologs
Species Human Mouse
Entrez 54984 72400
Ensembl ENSG00000254093 ENSMUSG00000021958
UniProt Q96BK5 Q9CZX5
RefSeq (mRNA) NM_001284356 NM_028228
RefSeq (protein) NP_001271285 NP_082504
Location (UCSC) Chr 8:
10.76 – 10.84 Mb		 Chr 14:
63.86 – 63.92 Mb
PubMed search

PIN2/TERF1-interacting telomerase inhibitor 1, also known as PINX1, is a human gene.[1] PINX1 is also known as PIN2 interacting protein 1.[2] PINX1 is a telomerase inhibitor and a possible tumor suppressor.

Interactions

PINX1 has been shown to interact with MCRS1,[3] TERF1[4] and telomerase reverse transcriptase.[4]

Structure

There are two known variants of PINX1. The second variant “lacks an exon in the 3’ coding region which results in a frameshift compared to variant 1. The encoded isoform is shorter and has a distinct C-terminus compared to isoform 1.”[2] There are three PINX1 cDNA clones. The longest one encodes a 328 amino acid 45kDa protein which contains an N-terminal Gly-rich patch and a C-terminal TID domain (telomerase inhibitory domain). The TRF1 binding domain is in the C-terminal 75 amino acids of PINX1. Mouse PINX1 is 74% identical to human PINX1. In other eukaryotes, including yeast, there is an overall 50% similarity to human PINX1.[4][5]

Function

Over-expression of PINX1 results in decreased telomerase activity, telomere shortening, and induction of crisis. Reduction of PINX1 leads to an increase in telomerase activity and elongation of telomeres. PINX1 differs from other proteins that regulate telomere length in that it acts on telomerase while other proteins adjust telomere length without affecting telomerase activity.[4]

The PINX1 budding yeast orthologue Gnop1 inhibits telomerase by isolating the uncomplexed TERT protein so that it cannot associate with the telomerase template RNA, which prevents telomerase from being assembled. However, in humans, PINX1 impedes already assembled telomerase. PINX1 binds to N-terminus of hTERT and binds to hTR in the presence of hTERT. PINX1 binding to hTR “is correlated to the repressive function of PINX1 on telomerase, implying that the mode of telomerase enzyme inhibition by PINX1 may involve an associated with hTR....The effect of hPINX1 on telomerase appears to be exclusive of the G-patch region and is mediated instead by the C terminus of the protein. This suggests that hPINX1 may have functionally separable cellular effects in which the N terminus is involved in RNA processing via the G-patch, and the C terminus is involved in telomere dynamics.”[6] It is suggested that “PINX1 represses telomerase activity in vivo by binding to the assembled hTERT-hTR complex.” [6]

The TID domain of PINX1 is likely what binds to hTERT. In cells, full-length PINX1 is not as strong as just the TID domain at inhibiting telomerase. This may be due to full-length PINX1 being subject to “endogenous regulation such as posttranslational modifications to reduce its inhibitory activity.”[4] Or it may be due to a reduction of the TID domain to bind and inhibit telomerase as a result of proteins interacting with PINX1, such as PIN2/TRF1 which colocalizes PINX1 in cells.[4]

There are two types of PINX1: nuclear PINX1 which is associates with telomeres and CAC repeats and nucleolar PINX1 does not bind directly to the telomeres, but instead interacts with TRF1. Nucleolar hPINX1 mediates the movement of hTERT and TRF1 to the nucleolus. Over-expression of nucleolar hPINX1 leads to increased TRF1 in the nucleolus and binding to telomeres. However, this accumulation in the nucleolus was not found in ALT (alternative lengthening of telomeres) cells indicating that PINX1 function is telomerase dependent.[7][8]

hPINX1 is found more in the nucleoplasm during the S phase which is also when telomerase is released into the nucleoplasm indicating that hPINX1 may inhibit telomerase during the S phase.[7]

Cancer

PINX1 is located at 8p23. Heterozygosity of this area is frequently lost in tumors including liver, prostate, prostate, colorectal, lung, and head and neck. Most PINX1 mutant tumors are carcinomas. PINX1 expression is significantly reduced in these tumors. This significance was shown with HT1080 cells, which increased tumorigenicity with decreased PINX1 expression. Over-expression of PINX1 in HT1080 cells did not allow them to form tumors in mice. Therefore, PINX1 may be a tumor suppressor.[4][9]

PINX1 expression is a predictor of cervical squamous cell carcinoma (CSCC) cells response to cisplatin/paclitaxel chemotherapy. High levels of PINX1 correlated to response. But the levels of PINX1 were only associated with cytotoxicity of paclitaxel. Reduced levels of PINX1 led to increased paclitaxel cytotoxicity. “The ability of PINX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel.”[10]

Chemoradiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma (ESCC). Reduced PINX1 expression did not affect ESCC cells response to 5-fluorouracil and cisplatin, but did increase efficacy of radiation therapy. High levels of PINX1 led to reduced cell death due to radiation. “PINX1 resistance to radiotherapy (RT) was attributed to PINX1 maintaining telomere stability, reducing ESCC cell death by RT-induced mitosis catastrophe.”[11] High levels of PINX1 is a predictor of short disease-specific survival.[11]

PINX1 levels were found to be reduced in urothelial carcinoma of the bladder (UCB) compared to normal urothelial bladder epithelium. “PINX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index, and poor survival.”[12] Over-expression of PINX1 reduced UCB cell proliferation and G1/S phase arrest. Knockdown PINX1 led to increased cell proliferation and accelerated G1/S transition.[12]

PinX1 in other cancers:

References

  1. ↑ "Entrez Gene: PINX1 PIN2-interacting protein 1".
  2. 1 2 "PINX1 PIN2/TERF1 interacting, telomerase inhibitor 1 [ Homo sapiens (human) ]". NCBI. Retrieved 2015-04-08.
  3. ↑ Song, Hai; Li Yiliang; Chen Guoyuan; Xing Zhen; Zhao Jing; Yokoyama Kazunari K; Li Tsaiping; Zhao Mujun (Apr 2004). "Human MCRS2, a cell-cycle-dependent protein, associates with LPTS/PinX1 and reduces the telomere length". Biochem. Biophys. Res. Commun. (United States) 316 (4): 1116–23. doi:10.1016/j.bbrc.2004.02.166. ISSN 0006-291X. PMID 15044100.
  4. 1 2 3 4 5 6 7 Zhou, X Z; Lu K P (Nov 2001). "The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor". Cell (United States) 107 (3): 347–59. doi:10.1016/S0092-8674(01)00538-4. ISSN 0092-8674. PMID 11701125.
  5. ↑ Soohoo, C.Y.; Shi, R.; Lee, T.H.; Huang, P.; Lu, K.P.; Zhou, X.Z. (November 2010). "Telomerase Inhibitor PinX1 Provides a Link between TRF1 and Telomerase to Prevent Telomere Elongation". Journal of Biological Chemistry. doi:10.1074/jbc.M110.180174. PMID 21119197. line feed character in |title= at position 56 (help)
  6. 1 2 Banik, S.S.R.; Counter, C.M. (September 2004). "Characterization of Interactions between PinX1 and Human Telomerase Subunits hTERT and hTR". Journal of Biological Chemistry. doi:10.1074/jbc.M408131200. PMID 15381700. line feed character in |title= at position 57 (help)
  7. 1 2 Yoo, J.E.; Oh, B.K.; Park, Y.N. (March 2009). "Human PinX1 Mediates TRF1 Accumulation in Nucleolus and Enhances TRF1 Binding to Telomeres". Journal of Molecular Biology. doi:10.1016/j.jmb.2009.02.051. line feed character in |title= at position 52 (help)
  8. ↑ Yoo, J.E.; Park, Y.N.; Oh, B.K. (January 2014). "PinX1, a Telomere Repeat-binding Factor 1 (TRF1)-interacting Protein, Maintains Telomere Integrity by Modulating TRF1 Homeostasis, the Process in Which Human Telomerase Reverse Transcriptase (hTERT) Plays Dual Roles". Journal of Biological Chemistry. doi:10.1074/jbc.M113.506006.
  9. ↑ Zhou, X.Z.; Huang, P.; Shi, R.; Lee, T.H.; Lu, G.; Zhang, Z.; Bronson, R.; Lu, K.P. (April 2011). "The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice". Journal of Clinical Investigation. doi:10.1172/JCI43452. PMID 21436583.
  10. ↑ Tian, X.P.; Qian, D.; He, L.R.; Huang, H.; Mai, S.J.; Li, C.P.; Huang, X.X.; Cai, M.Y.; Liao, Y.J. (July 2014). "The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas". Cancer Letters. doi:10.1016/j.canlet.2014.07.012. PMID 25045845.
  11. 1 2 Qian, D.; Zhang, B.; He, L.R.; Cai, M.Y.; Mai, S.J.; Liao, Y.J.; Liu, Y.H.; Lin, M.C.; Bian, X.W. (February 2013). "The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas". Journal of Pathology. doi:10.1002/path.4163. PMID 23341363. line feed character in |title= at position 61 (help)
  12. 1 2 Liu, J.Y.; Qian, D.; He, L.R.; Li, Y.H.; Liao, Y.J.; Mai, S.J.; Tian, X.P.; Liu, Y.H.; Zhang, J.X. (November 2013). "PinX1 suppresses bladder urothelial carcinoma cell proliferation via the inhibition of telomerase activity and p16/cyclin D1 pathway". Molecular Cancer. doi:10.1186/1476-4598-12-148. PMID 24268029.
  13. ↑ Cai, MY; Zhang, B.; He, W.P.; Yang, G.F.; Rao, H.L.; Rao, Z.Y.; Wu, Q.L.; Guan, X.Y.; Kung, H.F. (June 2010). "Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma". Cancer Science. doi:10.1111/j.1349-7006.2010.01560.x.
  14. ↑ Ma, Y.; Wu, L.; Liu, C.; Xu, L.; Li, D.; Li, J.C. (March 2009). "The correlation of genetic instability of PINX1 gene to clinico-pathological features of gastric cancer in the Chinese population". Journal of Cancer Research and Clinical Oncology. doi:10.1007/s00432-008-0471-6.
  15. ↑ Kondo, T; Oue, N.; Mitani, Y.; Kuniyasu, H.; Noguchi, T.; Kuraoka, K.; Nakayama, H.; Yasui, W. (January 2005). "Loss of heterozygosity and histone hypoacetylation of the PINX1 gene are associated with reduced expression in gastric carcinoma". Oncogene.
  16. ↑ Wang, H.B.; Wang, X.W.; Zhou, G.; Wang, W.Q.; Sun, Y.G.; Yang, S.M.; Fang, D.C. (August 2010). "PinX1 inhibits telomerase activity in gastric cancer cells through Mad1/c-Myc pathway". Journal of Gastrointestinal Surgery. doi:10.1007/s11605-010-1253-4.
  17. ↑ Zuo, J.; Wang, D.H.; Zhang, Y.J.; Liu, L.; Liu, F.L.; Liu, W. (October 2013). "Expression and mechanism of PinX1 and telomerase activity in the carcinogenesis of esophageal epithelial cells". Oncology Reports. doi:10.3892/or.2013.2649.
  18. ↑ Lai, X.F.; Shen, C.X.; Wen, Z.; Qian, Y.H.; Yu, C.S.; Wang, J.Q.; Zhong, P.N.; Wang, H.L. (February 2012). "PinX1 regulation of telomerase activity and apoptosis in nasopharyngeal carcinoma cells". Journal of Experimental and Clinical Cancer Research. doi:10.1186/1756-9966-31-12.
  19. ↑ Zhang, R.; Zhao, J.; Wang, X.; Wang, L.L.; Xu, J.; Song, C. (July 2014). "PinX1 without the G-patch motif suppresses proliferation, induces senescence, but does not inhibit telomerase activity in colorectal cancer SW480 cells". Oncology Reports. doi:10.3892/or.2014.3199.
  20. ↑ Wu, G.; Liu, D.; Jiang, K.; Zhang, L.; Zeng, Y.; Zhou, P.; Zhong, D.; Gao, M.; He, F. (February 2014). "PinX1, a novel target gene of p53, is suppressed by HPV16 E6 in cervical cancer cells". Biochimica et Biophysica Acta. doi:10.1016/j.bbagrm.2014.01.004.

Further reading

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