Mitogenic signal

Ambros If we knew what the mitogenic signal was we could ask whether the beginning of commitment to the secondary fate corresponds to this time. 

Irani, K. et al., Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts, Science, 275, 1649, 1997. 

A STRONG SUSTAINED MITOGENIC SIGNAL IS INDUCED BY MEMBRANE-BOUND CSE-1 IN SCA-1+ LIN- PRIMITIVE QUIESCENT STEM CELLS... 

Di Fiore, P. P., and G. N. Gill. Endocytosis and mitogenic signaling. Curt Opin Cell Biol. 11 483-488.1999. 

Mori, S., C. H. Heldin, and L. Claesson-Welsh. Ligand-induced ubiquitiruition of the platelet-derived growth factor beta-receptor plays a negative regulatory role in its mitogenic signaling. J Biol Chem. 268 577-83.1993. 

Berra E, Diaz-Meco MT, Dominguez I, Municio MM, Sanz L, Lozano J, Chapkin RS, Moscat J (1993) Protein kinase C zeta isoform is critical for mitogenic signal transduction. Cell 74 555-563... 

Several cancer cell types are characterized by expressing a truncated EGF receptor. The related viral oncogene, V-er B, also encodes a truncated receptor which lacks most of the extracellular domain (the EGF receptor is also known as C-erbB). Mutant receptors that display inappropriate constitutive activity can lead to cellular transformation, due to the continuous generation of mitogenic signal. 

At least four types of cytokine receptors can be differentiated on the basis of sequence homology (Fig. 11.2). Many members of the cytokine receptors of type 1 regulate growth and transmit mitogenic signals to the cell nucleus. The cytokine receptors of type 2 include the receptors for the interferons a and p. Type 3 includes the receptors for tiunor necrosis factor TNF and for CD 40 and Fas protein, which are foimd on T lymphocytes. 

Mitogenic Signals during Cell-cell Conununication... 

Continuous cell division is foimd, for example, in stem cells, which serve as precursors for other cells, and in tissue in which dying cells must be replaced. This requires the continuous effects of mitogenic signals. In this case, cell division must ensme homeostasis of the cell structure or the tissue. An increase in the cell number through cell division compensates for loss of cells that die as a part of normal cell turnover or that are eliminated by programmed cell death, or apoptosis. 

In the absence of external mitogenic signals or in the presence of a majority of antimi-togenic signals, cell division activity may be stopped. The cell enters the resting phase (Go phase). From Go phase, cell division may be resumed when mitogenic signals reappear. 

During the development of an organism, many cells enter a state of terminal differentiation, in which they perform a specialized function. Differentiated cells originate from dividing stem cells and in the process, partially or completely lose the abUity to divide. They are then no longer able to receive and act upon mitogenic signals. 

A change in the gene expression or stability of a proto-oncogene product may lead to an increase in the cellular concentration of the protein. Due to the increased concentration, a mitogenic signal mediated by a proto-oncogene product may be amplified. 

Fig. 14.3. Autocrine loops in tumor formation. Due to an error in control of transcription, growth factors may be produced and secreted in the cell which wonld normally only be formed in low concentrations or not at all. If the cell also possesses the receptors corresponding to the growth factor, the growth factor can then bind and activate a mitogenic signal chain. In this situation, the cell creates the mitogenic signal itself There is evidence that the growth factors can become active intracellularly. The mechanism behind this is nnknown.

If the path of a mitogenic signal is traced from the exterior to the interior of a cell at the level of the cell cycle and transcription, the proto-oncogenes may be categorized into the following groups (according to Himter, 1991) ... 

The activity of Ser/Thr-specific protein kinases is often controlled by autoinhibitory sequences (see 7.1.5). Loss or lack of function of autoregulatory sequences due to an oncogenic mutation can remove Ser/Hir kinase activity bound into mitogenic signaling pathways from normal control and thereby promote tumors. An example is the Raf kinase (see 9.6). Viral v-Raf oncoproteins are characterized by a deletion of the NH2-terminal regulatory sequences. 

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