Affinage

TCP10L

T-complex protein 10A homolog 1 · UniProt Q8TDR4

Length
215 aa
Mass
23.9 kDa
Annotated
2026-06-10
10 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCP10L is a nuclear, leucine zipper-containing transcriptional repressor expressed in liver and in the nucleus of spermatogenic cells, where it restrains cell growth and cell cycle progression (PMID:14586771, PMID:15910542, PMID:24565846). Its leucine zipper motif mediates homodimerization and is essential both for transcriptional repression activity and for protein-protein interactions, while nuclear localization is independent of this motif (PMID:14586771, PMID:17377852). Through its leucine zipper domain TCP10L engages the MYC-antagonizing transcription factors MAD4 and MAD1 as well as DAPK-3/ZIP kinase; binding to MAD1 stabilizes MAD1 protein levels and synergizes with it to drive transcriptional repression and G1 cell cycle arrest, an activity lost in interaction-deficient mutants (PMID:15469726, PMID:15910542, PMID:26698869). Consistent with this growth-suppressive role, TCP10L acts as a tumor suppressor in hepatocellular carcinoma, arresting cells at G0/G1 and suppressing colony formation and tumor growth, and its level is negatively controlled by NEK6, which binds and targets TCP10L for ubiquitination and degradation to relieve its suppression of tumorigenic and glycolytic programs (PMID:24565846, PMID:40228222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2003 Medium

    Established that TCP10L is a nuclear protein with intrinsic transcriptional repressor activity dependent on its leucine zipper, defining its core molecular function.

    Evidence Dual luciferase reporter assays with wild-type and leucine zipper mutant plus EGFP localization in HEK293, SK-HEP-1, and CHO cells

    PMID:14586771

    Open questions at the time
    • No direct DNA-binding target or promoter identified
    • Repression mechanism (co-repressor recruitment) not defined
  2. 2004 Medium

    Identified the first interaction partner, MAD4, linking TCP10L to the MYC/MAD transcriptional network.

    Evidence Yeast two-hybrid screen confirmed by co-immunoprecipitation and co-localization

    PMID:15469726

    Open questions at the time
    • Functional consequence of the MAD4 interaction not established
    • Interaction domain not mapped in this study
  3. 2005 Medium

    Showed TCP10L is expressed in spermatogenic cell nuclei and binds DAPK-3/ZIP kinase via its leucine zipper region, extending its partner repertoire to a kinase.

    Evidence Yeast two-hybrid, co-immunoprecipitation, localization, and mutagenesis

    PMID:15910542

    Open questions at the time
    • Functional outcome of DAPK-3 binding (phosphorylation of TCP10L?) not determined
    • Role in spermatogenesis not functionally tested
  4. 2007 Medium

    Resolved that the leucine zipper drives homodimerization but is dispensable for nuclear import, separating the dimerization function from localization.

    Evidence In vitro and in vivo homodimerization assays with leucine zipper deletion/point mutants and immunofluorescence in HeLa cells

    PMID:17377852

    Open questions at the time
    • Nuclear localization signal not mapped
    • Whether homodimers vs heterodimers dictate repressor activity unresolved
  5. 2014 Medium

    Demonstrated a physiological growth-suppressive role: TCP10L is a hepatocellular carcinoma tumor suppressor that enforces G0/G1 arrest.

    Evidence Overexpression and siRNA knockdown in HCC cells with colony formation, cell cycle analysis, and in vivo tumor growth assays

    PMID:24565846

    Open questions at the time
    • Direct downstream cell cycle effectors not identified
    • Link between transcriptional repression and arrest mechanistically unspecified
  6. 2016 Medium

    Provided the mechanistic basis for growth suppression: TCP10L binds and stabilizes MAD1 via leucine zipper domains and synergizes with it for repression and G1 arrest.

    Evidence Co-immunoprecipitation with domain mutants, luciferase repression assays, cell cycle analysis, and MAD1 Western blots

    PMID:26698869

    Open questions at the time
    • Mechanism by which TCP10L stabilizes MAD1 (blocking degradation?) not defined
    • Shared target genes of TCP10L/MAD1 not identified
  7. 2025 Medium

    Identified upstream regulation of TCP10L: NEK6 binds and ubiquitinates TCP10L for degradation, and restoring TCP10L reverses NEK6-driven tumorigenesis and glycolysis.

    Evidence Co-immunoprecipitation, ubiquitination assay, and NEK6 knockdown with TCP10L rescue in HCC cells

    PMID:40228222

    Open questions at the time
    • Whether NEK6 directly ubiquitinates or recruits an E3 ligase not resolved
    • Ubiquitination sites on TCP10L not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct DNA targets and the full transcriptional program controlled by TCP10L, and its in vivo function in spermatogenesis, remain undefined.
  • No ChIP/genome-wide target data
  • No organismal loss-of-function model
  • Mechanistic basis of testis-specific role unaddressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
DAPK3MAD1MAD4NEK6

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TCP10L encodes a leucine zipper-containing protein that localizes to the nucleus and functions as a transcriptional repressor; luciferase reporter assays showed ~2.6–9.8 fold repression of reporter gene expression in HEK293, SK-HEP-1, and CHO cells, and a leucine zipper mutant almost completely abolished this repression, indicating the leucine zipper is critical for transcriptional inhibition activity. Dual luciferase reporter assay with wild-type and leucine zipper mutant TCP10L; TCP10L-EGFP subcellular localization by fluorescence imaging Journal of human genetics Medium 14586771
2004 TCP10L physically interacts with MAD4 (a MYC-antagonizing transcription factor); interaction identified by yeast two-hybrid and confirmed by co-immunoprecipitation and co-localization experiments. Yeast two-hybrid screen, co-immunoprecipitation, subcellular localization Journal of biochemistry and molecular biology Medium 15469726
2005 TCP10L is expressed specifically in the nucleus of spermatogenic cells during spermatogenesis and binds to death-associated protein kinase 3 (DAPK-3/ZIP kinase); the interaction depends on the leucine zipper motif-containing region of TCP10L, as shown by mutagenesis. Yeast two-hybrid screening, co-immunoprecipitation, subcellular localization, mutagenesis International journal of andrology Medium 15910542
2007 TCP10L homodimerizes through its leucine zipper motif; deletion or point mutation of the leucine zipper abolishes homodimerization in vitro and in vivo, but leucine zipper mutants still localize to the nucleus, indicating the leucine zipper is required for dimerization but not for nuclear localization. In vitro and in vivo homodimerization assays, leucine zipper deletion and point mutation analysis, immunofluorescence in HeLa cells Molecular biology reports Medium 17377852
2014 TCP10L acts as a tumor suppressor in hepatocellular carcinoma by inhibiting cell cycle progression at G0/G1 phase; overexpression suppressed colony formation and attenuated cell growth in vivo, while silencing promoted cell cycle progression and cell growth. TCP10L overexpression and siRNA knockdown in HCC cells; colony formation assay, cell cycle analysis, in vivo tumor growth assay Biochemical and biophysical research communications Medium 24565846
2016 TCP10L interacts with MAD1 through their respective leucine zipper domains; TCP10L stabilizes intracellular MAD1 protein levels through this direct interaction, synergizes with MAD1 in transcriptional repression and G1 cell cycle arrest, and the interaction-deficient TCP10L mutant fails to stabilize MAD1 or suppress cell growth. Co-immunoprecipitation, leucine zipper domain mutants, luciferase transcriptional repression assay, cell cycle analysis, Western blot for MAD1 protein levels BMB reports Medium 26698869
2025 NEK6, a serine/threonine kinase, binds to TCP10L and degrades TCP10L protein through ubiquitination, thereby negatively regulating TCP10L expression; rescue experiments demonstrated that TCP10L reverses the pro-tumorigenic and pro-glycolytic effects of NEK6 in HCC cells. Co-immunoprecipitation (NEK6–TCP10L binding), ubiquitination assay, NEK6 knockdown with TCP10L rescue experiments in HCC cells Critical reviews in eukaryotic gene expression Medium 40228222

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers. Pathology oncology research : POR 47 28803425
2005 TCP10L is expressed specifically in spermatogenic cells and binds to death associated protein kinase-3. International journal of andrology 12 15910542
2007 Identification of TCP10L as primate-specific gene derived via segmental duplication and homodimerization of TCP10L through the leucine zipper motif. Molecular biology reports 6 17377852
2019 Novel Mutations Segregating with Complete Androgen Insensitivity Syndrome and their Molecular Characteristics. International journal of molecular sciences 5 31671693
2014 TCP10L acts as a tumor suppressor by inhibiting cell proliferation in hepatocellular carcinoma. Biochemical and biophysical research communications 5 24565846
2004 Human liver specific transcriptional factor TCP10L binds to MAD4. Journal of biochemistry and molecular biology 5 15469726
2003 Identification of a novel liver-specific expressed gene, TCP10L, encoding a human leucine zipper protein with transcription inhibition activity. Journal of human genetics 5 14586771
2025 NEK6 Accelerates Hepatocellular Carcinoma Progression and Glycolysis through Ubiquitination of TCP10L. Critical reviews in eukaryotic gene expression 3 40228222
2021 Whole-Genome Study of a Multigenerational Family with Essential Tremor. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 3 33947493
2016 TCP10L synergizes with MAD1 in transcriptional suppression and cell cycle arrest through mutual interaction. BMB reports 2 26698869

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