On the other hand, the expression of cytokine- and growth factor-related genes (CSF2, TNFSF11, INHA, IL-20, TLR3, etc.), of blood cell differentiation-related genes (e.g., MAP4K1, CD3G, MAL, TRL4, and IL-20), and of signal transduction-related genes (e.g., NOTCH4, SOCS5
, STAT3, and CD3G) were higher in HSPCs cultured with MSCs than in HSPCs cultured alone.
Indeed, CIS and SOCS2, SOCS1 and SOCS3, SOCS4 and SOCS5, and SOCS6 and SOCS7 all form related pairs .
For example, CIS, SOCS1, SOCS2, and SOCS3 have relatively short (50-80 residues) N-terminal regions, whereas SOCS4, SOCS5, SOCS6 and SOCS7 have longer N-terminal regions of up to 380 residues [22, 25, 26].
Most striking are the extended N-terminal regions of SOCS4 (270 aa), SOCS5 (368 aa), SOCS6 (369 aa), and SOCS7 (385 aa) (excluding the ESS), suggesting these four proteins form a subgroup within the SOCS family.
In Vitro Functions of SOCS4 and SOCS5. SOCS4 and SOCS5 share greater sequence similarity with each other than with other members of the SOCS family , with conservation largely restricted to the SH2 domain (92% amino acid identity) suggesting that while the SH2 domains may have an overlapping binding specificity , the N-terminal regions will have unique protein targets.
However, SOCS5 transgenic mice were found to have increased peritoneal IL2 and IFN-[gamma], cytokines involved in the promotion of Th1 differentiation , and SOCS6 was shown to bind to the kinase domain of active [p56.sup.lck], targeting it for ubiquitination and subsequent degradation, with SOCS6 overexpression resulting in repression of TCR-dependent IL-2 promoter activity .
In vivo functional redundancy may not only explain the obvious lack of effect in CIS, SOCS5, and SOCS6-deficient mice but also the apparent absence of roles for SOCS proteins in regulation of JAKSTAT-dependent cytokines such as EPO and TPO.
SOCS5, reported in this paper, is one of the several new "cooperating" cancer genes to be identified through this innovative approach.
Already, there are indications that levels of SOCS5 expression are reduced in breast cancer, and patients with low levels of SOCS5 have poor prognosis."
The IMCB team is preparing to explore the use of SOCS5 as a biomarker in diagnosis for cancer.