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From Proteopedia

Transitionally controlled tumor protein 1 (TCTP1/TPT1)

Function

TCTP1 is a highly conserved essential protein with a diverse range of cellular functions including cell growth, cell division and in the immune system as a histamine releasing factor. ^[1] anti-apoptotic protein that is known to play a key role in tumor growth. ^[2] High levels of expression TCTP1 are commonly seen in dividing cells, and it is overexpressed in tumor cells. ^[3] Decreased expression of TCTP1 in malignant cells has been identified as one possible mechanism of tumor reversion, where tumorgenic cancerous cells cease to be malignant. ^[4] Specifically, TCTP1 expression is almost undetectable in reverted cells. ^[5]

While many mammals, including humans have one copy of TCTP1, the capybara, the largest rodent has multiple copies of the TCTP1 gene. It is hypothesized that these multiple copies are one mechanism of cell proliferation and growth that enables the capybara to achieve such a large size. ^[6]

Disease

High level of TCTP expression in G3-breast tumors is associated with worse clinical outcomes (HR of 8.31 for a distant malignant event and 5.33 for a local re-occurrence compared to tumors with low TCTP expression). ^[7] Similar patterns have also been seen in ovarian cancer. In a Cox model that included FIGO stage, histolgoic grade, lymph node status, presence of ascites, tumor cells in peritoneal fluid, and ki-67 (an expression marker for malignant ovarian tumors), high levels of TCTP expression had a HR of 1.93 (95% CI: 1.11-3.36) compared to low levels of TCTP expression. ^[8]

Relevance

Multiple proposed mechanisms have been proposed to explain TCTP1's ability to help regulate tumorgenic activity. TCTP1 may interact with the pro-apoptotic factor Bax.

A second proposed mechanism may be in reciprocal repression with the tumor suppressor p53. ^[9] Specifically, TCTP may promote p53 degradation by promoting its ubiquitination by MDM2. ^[10] The specific structural mechanism for this has not been conclusively established.

Structural highlights

TCTP has three α helices and nine β strands arranged into two distorted β sheets. There are three major regions of TCTP: the N-terminal region (AA1-80), the central loop segment (81-130) and the C terminal region (131-172). There is a known interaction between the C-terminal and N-terminal.^[11] The most conserved sequence is in the middle of the protein (AA37-68), in an otherwise disordered region. ^[12] It is hypothesized that many of TCTP's binding interactions may occur there since this disordered region can be flexible, allowing it assume multiple different conformations for different binding partners. ^[13]

This area also contains Ser46, Ser64, as well as multiple glutemates and aspartates (Glu40, Asp44, Asp45, Glu55, Glu58, Glu60, Glu63) that may further enable multiple possible conformations that heavily influenced by phosphorylation of the serines and binding of positively charged ions such as calcium.

There is a second highly conserved area in the C terminal; this is sometimes referred to as TCTP2 (a second potential binding domain) from AAs 129 to 151.

TCTP1 is hypothesized to interact with Bax which has two helices (H5-H6) that are structurally very similar to the H2/H3 in TCTP1. It is hypothesized that TCTP1 may be able to interfere with Bax's homodimerization. Site direct mutagenesis of two key residues (E102 and K109) results in increased apoptosis.

References

1. ↑ Malard F, Assrir N, Alami M, Messaoudi S, Lescop E, Ha-Duong T. Conformational Ensemble and Biological Role of the TCTP Intrinsically Disordered Region: Influence of Calcium and Phosphorylation. J Mol Biol. 2018 May 25;430(11):1621-1639. doi: 10.1016/j.jmb.2018.04.024. Epub, 2018 Apr 30. PMID:29719201 doi:http://dx.doi.org/10.1016/j.jmb.2018.04.024
2. ↑ Tuynder M, Fiucci G, Prieur S, Lespagnol A, Geant A, Beaucourt S, Duflaut D, Besse S, Susini L, Cavarelli J, Moras D, Amson R, Telerman A. Translationally controlled tumor protein is a target of tumor reversion. Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15364-9. doi:, 10.1073/pnas.0406776101. Epub 2004 Oct 15. PMID:15489264 doi:http://dx.doi.org/10.1073/pnas.0406776101
3. ↑ Tuynder M, Fiucci G, Prieur S, Lespagnol A, Geant A, Beaucourt S, Duflaut D, Besse S, Susini L, Cavarelli J, Moras D, Amson R, Telerman A. Translationally controlled tumor protein is a target of tumor reversion. Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15364-9. doi:, 10.1073/pnas.0406776101. Epub 2004 Oct 15. PMID:15489264 doi:http://dx.doi.org/10.1073/pnas.0406776101
4. ↑ Amson R, Pece S, Lespagnol A, Vyas R, Mazzarol G, Tosoni D, Colaluca I, Viale G, Rodrigues-Ferreira S, Wynendaele J, Chaloin O, Hoebeke J, Marine JC, Di Fiore PP, Telerman A. Reciprocal repression between P53 and TCTP. Nat Med. 2011 Dec 11;18(1):91-9. doi: 10.1038/nm.2546. PMID:22157679 doi:http://dx.doi.org/10.1038/nm.2546
5. ↑ Amson R, Pece S, Lespagnol A, Vyas R, Mazzarol G, Tosoni D, Colaluca I, Viale G, Rodrigues-Ferreira S, Wynendaele J, Chaloin O, Hoebeke J, Marine JC, Di Fiore PP, Telerman A. Reciprocal repression between P53 and TCTP. Nat Med. 2011 Dec 11;18(1):91-9. doi: 10.1038/nm.2546. PMID:22157679 doi:http://dx.doi.org/10.1038/nm.2546
6. ↑ doi: https://dx.doi.org/10.1101/424606
7. ↑ . PMID:216315890657
8. ↑ Chen C, Deng Y, Hua M, Xi Q, Liu R, Yang S, Liu J, Zhong J, Tang M, Lu S, Zhang Z, Min X, Tang C, Wang Y. Expression and clinical role of TCTP in epithelial ovarian cancer. J Mol Histol. 2015 Apr;46(2):145-56. doi: 10.1007/s10735-014-9607-y. Epub 2015, Jan 7. PMID:25564355 doi:http://dx.doi.org/10.1007/s10735-014-9607-y
9. ↑ Amson R, Pece S, Lespagnol A, Vyas R, Mazzarol G, Tosoni D, Colaluca I, Viale G, Rodrigues-Ferreira S, Wynendaele J, Chaloin O, Hoebeke J, Marine JC, Di Fiore PP, Telerman A. Reciprocal repression between P53 and TCTP. Nat Med. 2011 Dec 11;18(1):91-9. doi: 10.1038/nm.2546. PMID:22157679 doi:http://dx.doi.org/10.1038/nm.2546
10. ↑ . PMID:216315890657
11. ↑ 10.1016/j.jmb.2018.04.024
12. ↑ 10.1016/j.jmb.2018.04.024
13. ↑ 10.1016/j.jmb.2018.04.024