Related Experiment Video

Updated: Aug 12, 2025

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
10:06

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

9.0K

Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation

Matthew J Cuneo1, Brian G O'Flynn1, Yu-Hua Lo1

  • 1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA.

Molecular Cell
|January 24, 2023
PubMed

Insights

Speckle-type POZ protein (SPOP) mutations linked to cancer were structurally analyzed. New insights reveal how SPOP self-assembly interfaces and oligomeric structure impact cancer development.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Biology

Background:

  • Speckle-type POZ protein (SPOP) is a substrate receptor for Cullin3-RING ubiquitin ligase (CRL3) complexes.
  • SPOP mutations are implicated in various cancers, including prostate and endometrial cancer, with unclear mechanisms for many mutations.

Purpose of the Study:

  • To elucidate the structural basis of SPOP function and the impact of cancer-associated mutations.
  • To investigate the oligomeric structure of SPOP and its role in protein self-assembly and function.

Main Methods:

  • X-ray crystallography to determine the structure of oligomeric SPOP.
  • Biochemical assays to analyze SPOP self-assembly, stability, and activity.

Main Results:

  • The first structure of oligomeric SPOP revealed novel interfaces crucial for self-assembly and function.
  • Cancer mutations, particularly in endometrial cancer, were mapped to these newly identified interfaces.
  • Structural and functional analyses demonstrated how mutations dysregulate SPOP through altered self-association, stability, and activity.

Conclusions:

  • The oligomeric structure and self-assembly interfaces of SPOP are critical for its normal function.
  • Dysregulation of these interfaces by cancer mutations provides a molecular mechanism for SPOP's role in tumorigenesis.
  • Understanding these mechanisms opens new avenues for therapeutic strategies targeting SPOP in cancer.
Keywords:
cryo-EMendometrial cancerfilamentgain of functionhigher-order oligomerhypermorphiconcogeneprostate cancerstructuretumor suppressor

More Related Videos

Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel08:29

Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel

Published on: May 14, 2018

10.0K
Observing Mitotic Division and Dynamics in a Live Zebrafish Embryo10:10

Observing Mitotic Division and Dynamics in a Live Zebrafish Embryo

Published on: July 15, 2016

12.2K

Related Concept Videos

Cancers Originate from Somatic Mutations in a Single Cell02:21

Cancers Originate from Somatic Mutations in a Single Cell

Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
12.4K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.1K
Abnormal Cell Divisions01:22

Abnormal Cell Divisions

Abnormal Cell DivisionsCell division is a normal process that enables organisms to grow, repair tissues, and replace old cells. However, in some cases, cells divide uncontrollably, leading to abnormal cell growth. This can result in conditions such as tumors, cancer, or genetic disorders. Abnormal cell division occurs when the regulatory mechanisms that control the cell cycle fail, allowing cells to multiply without restriction. Scientists can create new treatments for diseases, conduct further...
4
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
7.6K
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
9.1K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
4.3K