Thyroid Hormone Receptor Mutations in Cancer and Resistance to Thyroid Hormone: Perspective and Prognosis
Figure 4
Oncogenic- and RTH-associated mutations in different TR isoforms. (a) A schematic of wild-type TRα1 is shown as a horizontal bar as in Figure 1; beneath, horizontal lines depict v-Erb A and several representative HCC/RCCC TRα1 mutants. As a result of fusion of retroviral gag-sequences, the N-terminus of v-erb A is 12 amino acids shorter than TRα1. V-erb A’s 13 mutations are indicated by black arrowheads. From left to right, they are R24H, Y44C, G73S, K90T, K186R, P191L, P203L, K233N, T342S, P363S, T370A, C378Y, and F395S. A 9 amino-acid C-terminal deletion is indicated by vertical lines. All mutations and deletions are in relation to the avian TRα1 sequence [24]. Under the schematic for v-Erb A, red and blue arrowheads indicate mutations found in representative HCC and RCCC mutants, respectively, [37–39]. The nomenclature for each mutant is provided at the far right of the figure. For HCC, these mutants are hcI-TRα1 (K74E, A264V) and hcM-TRα1 (K74R, M150T, and E159K). For RCCC, these mutants are rc2-TRα1 (I116N and M388I) and rc6-TRα1 (I116N, A225T, and M388I). (b) A schematic of wild-type TRβ1 is shown as a horizontal bar as in Figure 1; beneath, horizontal lines depict several representative HCC/RCCC TRβ mutants, RTH hot spots, and the RTH mutant, TRβ1-PV. As above, red and blue arrowheads indicate representative mutations found in HCC and RCCC [37–39]. For HCC, these mutants are hcE-TRβ1 (M32I, C107R, and T368N), hcI-TRβ1 (S43L, C446R), hcJ-TRβ1 (M313I), and hcN-TRβ1 (K113N and T329P). For RCCC, these mutants are rc8-TRβ1 (F451S), rc15-TRβ1 (K155E, K411E), and rc25-TRβ1 (Y321H). Below the schematic for HCC/RCCC mutants, the locations of RTH hot spots are shown (amino acids 234–282, 310–353, and 429–460 [36]). Representative mutants for PRTH are: R338L, R383H, and R429Q. For GRTH, these mutations are G345S and P453S. The TRβ1-PV mutant has undergone a C-insertion at codon 448 that results in a frameshift at the C-terminus of the receptor [40]. The location of the 16 new PV-specific amino acids is indicated by a black box on the TRβ1-PV schematic, and the identities of these amino acids (and their wild-type TRβ1 counterparts) are shown below. The TRβ1-Mkar mutant has a T insertion at codon 436 that results in a frameshift at the C-terminus of the receptor. The locations of these new 28 amino acids are indicated by a black box on the TRβ1-Mkar schematic, and their identities are shown below. Note that Mkar shares with PV the amino acid sequence from codons 448 to 463 [41].
