Intestinal Cell Proliferation and Differentiation

This assignment delves into the intricate processes of intestinal cell proliferation and differentiation. It examines various growth factors like EGFR and FGFs, their roles in stimulating cell division, and how they influence downstream signaling pathways such as Wnt/Wg and MAPK. The impact of a high-fat diet on both proliferation and differentiation is also discussed, highlighting its effect on stem cells and the development of colorectal cancer.

Running head: CELL PROLIFERATION AND DIFFERENTIATION
Intestinal cell proliferation and differentiation
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1CELL PROLIFERATION AND DIFFERENTIATION
Intestinal cell proliferation
Several growth factors mediate the process of proliferation that triggers cells to enter cell
cycle. Proliferation of the mucosal cells is needed to maintain the integrity of the gastrointestinal
system. The EFGR gene sends instruction for production of the Epidermal growth factor receptor
protein, which promotes cell proliferation. It is a transmembrane protein and is activated by
specific ligand binding. Upon activation, EGFR undergoes dimerization, which stimulates
tyrosine kinase activity. The tyrosine residues get autophosphorylated and activate downstream
signaling of other pathways and promote proliferation. Receptor tyrosine kinase also influences
the activity of insulin-like growth factor 1 and 2 encoded by the IGFR1 and IGFR2 genes
respectively. Binding of ligand activates the receptor tyrosine kinase, autophosphoryaltion
initiates intracellular signalling and activates the Akt and Ras MAPK pathway (Waseem et al.
2014). This increases proliferation and inhibits apoptosis. KLF4 or Krupple like factor 4 is a
zinc-finger transcription factor, involved in regulation of proliferation. KLF4 is expressed in non-
dividing cells of the intestinal epithelium and maintains homeostasis in these cells. In the
intestinal epithelium, it regulates Wnt signaling pathway of genes. Fibroblast growth factors
(FGRFR2 and FGFR4) controls intestinal cell proliferation by binding to the receptor tyrosine
kinase family. LGR5 promotes proliferation by acceleration of cell cycle. The main effect of
high fat diet occurs in the colon, which leads to enhanced cell proliferation. Total lipids in feces
are measured by a gravimetric method. Diet rich in saturated fats excerete more lipids.
Proliferation of distal colon cell increases as fecal lipids increase (Sakar et al.2014).

2CELL PROLIFERATION AND DIFFERENTIATION
Intestinal cell differentiation
A cell becomes more specialized through the process of differentiation. The EGFR, FGF-
2, FGF-4, KLF4, HNF1a are responsible fot influencing the differentiation pathways of intestinal
cells. Binding of specific ligands to the receptors encoded by these genes triggers the tyrosine
kinsase activity. This activation occurs through dimerization of the receptors. Dimerization is
followed by autophosphorylation and activation of downstream signaling pathways like Notch,
BMP, Wnt/Wg, Hedgehog (Hh), mitogen-activated protein kinase (MAPK) and other pathways.
Crypt structures and transient amplifying cells were rapidly lost due to block of the
β-catenin/Wnt signaling (Barker 2014). β-Catenin is a cytoplasmic signal-transducer of the
canonical Wnt pathway. In the absence of Wnt ligands, β-catenin is phosphorylated and
degraded. The degradation complex contains the tumor suppressor gene products conductin or
axin, APC (adenomatous polyposis coli), casein kinase I (CKI) and glycogen synthase kinase 3β.
When the Wnt ligand binds to Frizzled transmembrane receptors, Disheveled cytoplasmic
protein gets activated. It blocks the function of the degradation complex. β-Catenin enters the
nucleus and associates with LEF/TCF transcription factors. It induces transcriptional control of
the Wnt target genes. Mutations which activate this pathway initiates colorectal cancer. The
tumors are manifested by truncated mutation in axin and APC. Recently, several studies have
reported that intestinal stem cells get inflamed and their differentiation is directly effected by
prolonged consumption of saturated fat diet (Beyaz et al. 2016).

3CELL PROLIFERATION AND DIFFERENTIATION
References
Barker, N., 2014. Adult intestinal stem cells: critical drivers of epithelial homeostasis and
regeneration. Nature reviews. Molecular cell biology, 15(1), p.19.
Beyaz, S., Mana, M.D., Roper, J., Kedrin, D., Saadatpour, A., Hong, S.J., Bauer-Rowe, K.E.,
Xifaras, M.E., Akkad, A., Arias, E. and Pinello, L., 2016. High fat diet enhances stemness and
tumorigenicity of intestinal progenitors. Nature, 531(7592), p.53.
Sakar, Y., Duca, F.A., Langelier, B., Devime, F., Blottiere, H., Delorme, C., Renault, P. and
Covasa, M., 2014. Impact of high-fat feeding on basic helix-loop-helix transcription factors
controlling enteroendocrine cell differentiation. International journal of obesity, 38(11), p.1440.
Waseem, T., Duxbury, M., Ashley, S.W. and Robinson, M.K., 2014. Ghrelin promotes intestinal
epithelial cell proliferation through PI3K/Akt pathway and EGFR trans-activation both
converging to ERK 1/2 phosphorylation. Peptides, 52, pp.113-121.