Related Experiment Video

Updated: May 22, 2026

Protocols for Analyzing the Role of Paneth Cells in Regenerating the Murine Intestine using Conditional Cre-lox Mouse Models
07:48

Protocols for Analyzing the Role of Paneth Cells in Regenerating the Murine Intestine using Conditional Cre-lox Mouse Models

Published on: November 21, 2015

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

O N Demidov1, Y Zhu, C Kek

  • 1Institute of Molecular and Cell Biology, Cell Cycle Control and Tumorigenesis Group, Singapore 138673, Singapore.

Cell Death and Differentiation
|May 5, 2012
PubMed

Insights

Wild-type p53-induced phosphatase 1 (Wip1) suppresses intestinal stem cell conversion into tumor-initiating cells. Deleting Wip1 enhances tumor resistance, with Gadd45a playing a key role in this process.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Intestinal stem cell conversion to tumor-initiating cells is an early step in Apc(Min)-induced polyposis.
  • Wild-type p53-induced phosphatase 1 (Wip1) and p53 are crucial for suppressing stem cell conversion.
  • Wip1 deletion reduces tumor burden in Apc(Min) mice, indicating its role in tumor suppression.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying Wip1-dependent tumor resistance.
  • To identify genes critical for the tumor-resistant phenotype observed in Wip1-deficient mice.
  • To elucidate the role of Gadd45a in Wip1-mediated tumor suppression and its interaction with p53 and beta-catenin signaling.

Main Methods:

  • Analysis of Wip1-deficient Apc(Min) mice.
  • Assessment of the roles of cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and Gadd45a.
  • Investigation of Gadd45a's function via the Jnk signaling pathway.
  • Evaluation of p53's proapoptotic functions in response to beta-catenin activation.

Main Results:

  • Cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and Gadd45a are essential for the tumor-resistant phenotype in Wip1-deficient mice.
  • Gadd45a acts as a haploinsufficient gene in regulating Wip1-dependent tumor resistance.
  • Gadd45a activates the Jnk pathway, mediating p53's proapoptotic functions in response to beta-catenin signaling.
  • Silencing Gadd45a overrides p53 activation under conditions of active beta-catenin and enhanced DNA damage response.

Conclusions:

  • Gadd45a is a critical mediator of Wip1-dependent tumor resistance in the intestine.
  • The interplay between Gadd45a, Jnk, p53, and beta-catenin signaling is vital for controlling intestinal polyposis.
  • Targeting Gadd45a may offer therapeutic strategies for Wip1-related cancers.

More Related Videos

Real-time Imaging of Myeloid Cells Dynamics in ApcMin/+ Intestinal Tumors by Spinning Disk Confocal Microscopy05:21

Real-time Imaging of Myeloid Cells Dynamics in ApcMin/+ Intestinal Tumors by Spinning Disk Confocal Microscopy

Published on: October 6, 2014

In vitro Organoid Culture of Primary Mouse Colon Tumors07:33

In vitro Organoid Culture of Primary Mouse Colon Tumors

Published on: May 17, 2013

Related Concept Videos

Canonical Wnt Signaling Pathway02:54

Canonical Wnt Signaling Pathway

The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which results in tumor...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Role Of Notch Signalling In Intestinal Stem Cell Renewal01:12

Role Of Notch Signalling In Intestinal Stem Cell Renewal

Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
Pleiotropy01:33

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal01:22

Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal

Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.